Aminotetrahydropyrans as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes

ABSTRACT

The present invention is directed to novel substituted aminotetrahydropyrans of structural formula I which are inhibitors of the dipeptidyl peptidase-IV enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of application U.S. Ser. No.13/398,887 which is a continuation of U.S. application Ser. No.12/616,831 which granted as U.S. Pat. No. 8,143,289 which claimspriority to U.S. provisional application Ser. No. 61/199,179, filed Nov.13, 2008, the contents of which are hereby incorporated by reference intheir entirety.

FIELD OF THE INVENTION

The present invention relates to novel substituted aminotetrahydropyranswhich are inhibitors of the dipeptidyl peptidase-IV enzyme (“DPP-4inhibitors”) and which are useful in the treatment or prevention ofdiseases in which the dipeptidyl peptidase-IV enzyme is involved, suchas diabetes and particularly Type 2 diabetes. The invention is alsodirected to pharmaceutical compositions comprising these compounds andthe use of these compounds and compositions in the prevention ortreatment of such diseases in which the dipeptidyl peptidase-IV enzymeis involved.

BACKGROUND OF THE INVENTION

Diabetes refers to a disease process derived from multiple causativefactors and characterized by elevated levels of plasma glucose orhyperglycemia in the fasting state or after administration of glucoseduring an oral glucose tolerance test. Persistent or uncontrolledhyperglycemia is associated with increased and premature morbidity andmortality. Often abnormal glucose homeostasis is associated bothdirectly and indirectly with alterations of the lipid, lipoprotein andapolipoprotein metabolism and other metabolic and hemodynamic disease.Therefore patients with Type 2 diabetes mellitus are at especiallyincreased risk of macrovascular and microvascular complications,including coronary heart disease, stroke, peripheral vascular disease,hypertension, nephropathy, neuropathy, and retinopathy. Therefore,therapeutical control of glucose homeostasis, lipid metabolism andhypertension are critically important in the clinical management andtreatment of diabetes mellitus.

There are two generally recognized forms of diabetes. In Type 1diabetes, or insulin-dependent diabetes mellitus (IDDM), patientsproduce little or no insulin, the hormone which regulates glucoseutilization. In Type 2 diabetes, or noninsulin dependent diabetesmellitus (NIDDM), patients often have plasma insulin levels that are thesame or even elevated compared to nondiabetic subjects; however, thesepatients have developed a resistance to the insulin stimulating effecton glucose and lipid metabolism in the main insulin-sensitive tissues,which are muscle, liver and adipose tissues, and the plasma insulinlevels, while elevated, are insufficient to overcome the pronouncedinsulin resistance.

Insulin resistance is not primarily due to a diminished number ofinsulin receptors but to a post-insulin receptor binding defect that isnot yet understood. This resistance to insulin responsiveness results ininsufficient insulin activation of glucose uptake, oxidation and storagein muscle and inadequate insulin repression of lipolysis in adiposetissue and of glucose production and secretion in the liver.

The available treatments for Type 2 diabetes, which have not changedsubstantially in many years, have recognized limitations. While physicalexercise and reductions in dietary intake of calories will dramaticallyimprove the diabetic condition, compliance with this treatment is verypoor because of well-entrenched sedentary lifestyles and excess foodconsumption, especially of foods containing high amounts of saturatedfat. Increasing the plasma level of insulin by administration ofsulfonylureas (e.g. tolbutamide and glipizide) or meglitinide, whichstimulate the pancreatic β cells to secrete more insulin, and/or byinjection of insulin when sulfonylureas or meglitinide becomeineffective, can result in insulin concentrations high enough tostimulate the very insulin-resistant tissues. However, dangerously lowlevels of plasma glucose can result from administration of insulin orinsulin secretagogues (sulfonylureas or meglitinide), and an increasedlevel of insulin resistance due to the even higher plasma insulin levelscan occur. The biguanides increase insulin sensitivity resulting in somecorrection of hyperglycemia. However, the two biguanides, phenformin andmetformin, can induce lactic acidosis and nausea/diarrhea. Metformin hasfewer side effects than phenformin and is often prescribed for thetreatment of Type 2 diabetes.

The glitazones (i.e. 5-benzylthiazolidine-2,4-diones) constitute anadditional class of compounds with potential for ameliorating manysymptoms of Type 2 diabetes. These agents substantially increase insulinsensitivity in muscle, liver and adipose tissue in several animal modelsof Type 2 diabetes resulting in partial or complete correction of theelevated plasma levels of glucose without occurrence of hypoglycemia.The glitazones that are currently marketed are agonists of theperoxisome proliferator activated receptor (PPAR), primarily thePPAR-gamma subtype. PPAR-gamma agonism is generally believed to beresponsible for the improved insulin sensititization that is observedwith the glitazones. Newer PPAR agonists that are being tested fortreatment of Type 2 diabetes are agonists of the alpha, gamma or deltasubtype, or a combination of these, and in many cases are chemicallydifferent from the glitazones (i.e., they are not thiazolidinediones instructure). Serious side effects (e.g. liver toxicity) have occurredwith some of the glitazones, such as troglitazone.

Additional methods of treating the disease are still underinvestigation. New biochemical approaches that have been recentlyintroduced or are still under development include alpha-glucosidaseinhibitors (e.g. acarbose), GLP-1 mimetics (eg., exenatide andliraglutide), glucagon receptor antagonists, glucokinase activators, andGPR-119 agonists.

Compounds that are inhibitors of the dipeptidyl peptidase-IV (“DPP-4”)enzyme have also been found useful for the treatment of diabetes,particularly Type 2 diabetes [See WO 97/40832; WO 98/19998; U.S. Pat.No. 5,939,560; U.S. Pat. No. 6,303,661; U.S. Pat. No. 6,699,871; U.S.Pat. No. 6,166,063; Bioorg. Med. Chem. Lett., 6: 1163-1166 (1996);Bioorg. Med. Chem. Lett., 6: 2745-2748 (1996); D. J. Drucker in Exp.Opin. Invest. Drugs, 12: 87-100 (2003); K. Augustyns, et al., Exp. Opin.Ther. Patents, 13: 499-510 (2003); Ann E. Weber, J. Med. Chem., 47:4135-4141 (2004); J. J. Hoist, Exp. Opin. Emerg. Drugs, 9: 155-166(2004); D. Kim, et al., J. Med. Chem., 48: 141-151 (2005); K. Augustyns,Exp. Opin. Ther. Patents, 15: 1387-1407 (2005); H.-U. Demuth in Biochim.Biophys. Acta, 1751: 33-44 (2005); and R. Mentlein, Exp. Opin. Invest.Drugs, 14: 57-64 (2005).

Additional patent publications that disclose DPP-4 inhibitors useful forthe treatment of diabetes are the following: WO 2006/009886 (26 Jan.2006); WO 2006/039325 (13 Apr. 2006); WO 2006/058064 (1 Jun. 2006); WO2006/127530 (30 Nov. 2006); WO 2007/024993 (1 Mar. 2007); WO 2007/070434(21 Jun. 2007); WO 2007/087231 (2 Aug. 2007); WO 07/097,931 (30 Aug.2007); WO 07/126,745 (8 Nov. 2007); WO 07/136,603 (29 Nov. 2007); and WO08/060,488 (22 May 2008).

The usefulness of DPP-4 inhibitors in the treatment of Type 2 diabetesis based on the fact that DPP-4 in vivo readily inactivates glucagonlike peptide-1 (GLP-1) and gastric inhibitory peptide (GIP). GLP-1 andGIP are incretins and are produced when food is consumed. The incretinsstimulate production of insulin. Inhibition of DPP-4 leads to decreasedinactivation of the incretins, and this in turn results in increasedeffectiveness of the incretins in stimulating production of insulin bythe pancreas. DPP-4 inhibition therefore results in an increased levelof serum insulin. Advantageously, since the incretins are produced bythe body only when food is consumed, DPP-4 inhibition is not expected toincrease the level of insulin at inappropriate times, such as betweenmeals, which can lead to excessively low blood sugar (hypoglycemia).Inhibition of DPP-4 is therefore expected to increase insulin withoutincreasing the risk of hypoglycemia, which is a dangerous side effectassociated with the use of insulin secretagogues.

DPP-4 inhibitors also have other therapeutic utilities, as discussedherein. New compounds are needed so that improved DPP-4 inhibitors canbe found for the treatment of diabetes and potentially other diseasesand conditions. In particular, there is a need for DPP-4 inhibitors thatare selective over other members of the family of serine peptidases thatincludes quiescent cell proline dipeptidase (QPP), DPP8, and DPP9 [seeG. Lankas, et al., “Dipeptidyl Peptidase-IV Inhibition for the Treatmentof Type 2 Diabetes: Potential Importance of Selectivity Over DipeptidylPeptidases 8 and 9,” Diabetes, 54: 2988-2994 (2005); N. S. Kang, et al.,“Docking-based 3D-QSAR study for selectivity of DPP4, DPP8, and DPP9inhibitors,” Bioorg. Med. Chem. Lett., 17: 3716-3721 (2007)].

The therapeutic potential of DPP-4 inhibitors for the treatment of Type2 diabetes is discussed by (i) D. J. Drucker, Exp. Opin. Invest. Drugs,12: 87-100 (2003); (ii) K. Augustyns, et al., Exp. Opin. Ther. Patents,13: 499-510 (2003); (iii) J. J. Holst, Exp. Opin. Emerg. Drugs, 9:155-166 (2004); (iv) H.-U. Demuth, et al., Biochim. Biophys. Acta, 1751:33-44 (2005); (v) R. Mentlein, Exp. Opin. Invest. Drugs, 14: 57-64(2005); (vi) K. Augustyns, “Inhibitors of proline-specific dipeptidylpeptidases: DPP IV inhibitors as a novel approach for the treatment ofType 2 diabetes,” Exp. Opin. Ther. Patents, 15: 1387-1407 (2005); (vii)D. J. Drucker and M. A. Nauck, “The incretin system: GLP-1 receptoragonists and dipeptidyl peptidase-4 inhibitors in Type 2 diabetes,” TheLancet, 368: 1696-1705 (2006); (viii) T. W. von Geldern and J. M.Trevillyan, ““The Next Big Thing” in Diabetes: Clinical Progress onDPP-IV Inhibitors,” Drug Dev. Res., 67: 627-642 (2006); (ix) B. D. Greenet al., “Inhibition of dipeptidyl peptidase IV activity as a therapy ofType 2 diabetes,” Exp. Opin. Emerging Drugs, 11: 525-539 (2006); (x) J.J. Hoist and C. F. Deacon, “New Horizons in Diabetes Therapy,” Immun.,Endoc. & Metab. Agents in Med. Chem., 7: 49-55 (2007); (xi) R. K.Campbell, “Rationale for Dipeptidyl Peptidase 4 Inhibitors: a New Classof Oral Agents for the Treatment of Type 2 Diabetes Mellitus,” Ann.Pharmacother., 41: 51-60 (2007); (xii) Z. Pei, “From the bench to thebedside: Dipeptidyl peptidase IV inhibitors, a new class of oralantihyperglycemic agents,” Curr. Opin. Drug Discovery Development, 11:512-532 (2008); and (xiii) J. J. Hoist, et al., “Glucagon-likepeptide-1, glucose homeostasis, and diabetes, Trends in MolecularMedicine, 14: 161-168 (2008). Specific DPP-4 inhibitors either alreadyapproved or under clinical investigation for the treatment of Type 2diabetes include sitagliptin, vildagliptin, saxagliptin, alogliptin,carmegliptin, melogliptin, and dutogliptin.

SUMMARY OF THE INVENTION

The present invention is directed to novel substituted3-aminotetrahydropyrans which are inhibitors of the dipeptidylpeptidase-IV enzyme (“DPP-4 inhibitors”) and which are useful in thetreatment or prevention of diseases in which the dipeptidyl peptidase-Wenzyme is involved, such as diabetes and particularly Type 2 diabetes.The invention is also directed to pharmaceutical compositions comprisingthese compounds and the use of these compounds and compositions in theprevention or treatment of such diseases in which the dipeptidylpeptidase-IV enzyme is involved.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to novel substituted3-aminotetrahydropyrans that are useful as inhibitors of dipeptidylpeptidase-IV. Compounds of the present invention are described bystructural formula I:

and pharmaceutically acceptable salts thereof; whereinV is selected from the group consisting of:

Ar is phenyl optionally substituted with one to five R¹ substituents;each R¹ is independently selected from the group consisting of:

-   -   halogen,    -   cyano,    -   hydroxy,    -   C₁₋₆ alkyl, optionally substituted with one to five fluorines,        and    -   C₁₋₆ alkoxy, optionally substituted with one to five fluorines;        each R² is independently selected from the group consisting of    -   hydrogen,    -   halogen,    -   cyano,    -   C₁₋₁₀ alkoxy, wherein alkoxy is optionally substituted with one        to five substituents independently selected from fluorine and        hydroxy,    -   C₁₋₁₀ alkyl, wherein alkyl is optionally substituted with one to        five substituents independently selected from fluorine and        hydroxy,    -   C₂₋₁₀ alkenyl, wherein alkenyl is optionally substituted with        one to five substituents independently selected from fluorine        and hydroxy,    -   (CH₂)_(n)-aryl, wherein aryl is optionally substituted with one        to five substituents independently selected hydroxy, halogen,        cyano, nitro, CO₂H, C₁₋₆ alkyloxycarbonyl, C₁₋₆ alkyl, and C₁₋₆        alkoxy, wherein alkyl and alkoxy are optionally substituted with        one to five fluorines,    -   (CH₂)_(n)-heteroaryl, wherein heteroaryl is optionally        substituted with one to three substituents independently        selected from hydroxy, halogen, cyano, nitro, CO₂H, C₁₋₆        alkyloxycarbonyl, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl and        alkoxy are optionally substituted with one to five fluorines,    -   (CH₂)_(n)-heterocyclyl, wherein heterocyclyl is optionally        substituted with one to three substituents independently        selected from oxo, hydroxy, halogen, cyano, nitro, CO₂H, C₁₋₆        alkyloxycarbonyl, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl and        alkoxy are optionally substituted with one to five fluorines,    -   (CH₂)_(n)—C₃₋₆ cycloalkyl, wherein cycloalkyl is optionally        substituted with one to three substituents independently        selected from halogen, hydroxy, cyano, nitro, CO₂H, C₁₋₆        alkyloxycarbonyl, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein alkyl and        alkoxy are optionally substituted with one to five fluorines,    -   (CH₂)_(n)—COOH,    -   (CH₂)_(n)—COOC₁₋₆ alkyl,    -   (CH₂)_(n)—NR⁴R⁵,    -   (CH₂)_(n)—CONR⁴R⁵,    -   (CH₂)_(n)—OCONR⁴R⁵,    -   (CH₂)_(n)—SO₂NR⁴R⁵,    -   (CH₂)_(n)—SO₂R⁶,    -   (CH₂)_(n)—NR⁷SO₂R⁶,    -   (CH₂)_(n)—NR⁷CONR⁴R⁵,    -   (CH₂)_(n)—NR⁷COR⁷, and    -   (CH₂)_(n)—NR⁷CO₂R⁶;        wherein any individual methylene (CH₂) carbon atom in (CH₂)_(n)        is optionally substituted with one to two substituents        independently selected from fluorine, hydroxy, C₁₋₄ alkyl, and        C₁₋₄ alkoxy, wherein alkyl and alkoxy are optionally substituted        with one to five fluorines;        R^(3a) and R^(3b) are each independently hydrogen or C₁₋₄ alkyl        optionally substituted with one to five fluorines;        R⁴ and R⁵ are each independently selected from the group        consisting of    -   hydrogen,    -   (CH₂)_(m)-phenyl,    -   (CH₂)_(m)—C₃₋₆ cycloalkyl, and    -   C₁₋₆ alkyl, wherein alkyl is optionally substituted with one to        five substituents independently selected from fluorine and        hydroxy and wherein phenyl and cycloalkyl are optionally        substituted with one to five substituents independently selected        from halogen, hydroxy, C₁₋₆ alkyl, and C₁₋₆ alkoxy, wherein        alkyl and alkoxy are optionally substituted with one to five        fluorines;        or R⁴ and R⁵ together with the nitrogen atom to which they are        attached form a heterocyclic ring selected from azetidine,        pyrrolidine, piperidine, piperazine, and morpholine wherein said        heterocyclic ring is optionally substituted with one to three        substituents independently selected from halogen, hydroxy, C₁₋₆        alkyl, and C₁₋₆ alkoxy, wherein alkyl and alkoxy are optionally        substituted with one to five fluorines;        each R⁶ is independently C₁₋₆ alkyl, wherein alkyl is optionally        substituted with one to five substituents independently selected        from fluorine and hydroxyl;        R⁷ is hydrogen or R⁶;        R⁸ is selected from the group consisting of:    -   —SO₂C₁₋₆ alkyl,    -   —SO₂C₃₋₆ cycloalkyl,    -   —SO₂-aryl,    -   —SO₂-heteroaryl,    -   —C(O)C₁₋₆ alkyl,    -   —C(O)C₃₋₆ cycloalkyl,    -   —C(O)-aryl,    -   —C(O)-heteroaryl,    -   —C(O)OC₁₋₆ alkyl,    -   —C(O)OC₃₋₆ cycloalkyl,    -   —C(O)O-aryl,    -   —C(O)O-heteroaryl,    -   —C(O)NHC₁₋₆ alkyl,    -   —C(O)NHC₃₋₆ cycloalkyl,    -   —C(O)NH-aryl, and    -   —C(O)NH-heteroaryl;        wherein alkyl and cycloalkyl are optionally substituted with one        to five fluorines and wherein aryl and heteroaryl are optionally        substituted with one to five substituents independently selected        from the group consisting of hydroxy, halogen, cyano, nitro,        CO₂H, C₁₋₆ alkyloxycarbonyl, C₁₋₆ alkyl, and C₁₋₆ alkoxy,        wherein alkyl and alkoxy are optionally substituted with one to        five fluorines;        each n is independently 0, 1, 2 or 3; and        each m is independently 0, 1, or 2.

In one embodiment of the compounds of the present invention, Ar isoptionally substituted with one to three substituents independentlyselected from the group consisting of fluorine, chlorine, bromine,methyl, trifluoromethyl, and trifluoromethoxy. In a class of thisembodiment, Ar is 2,5-difluorophenyl or 2,4,5-trifluorophenyl.

In a second embodiment of the compounds of the present invention, R^(3a)and R^(3b) are both hydrogen.

In a third embodiment of the compounds of the present invention, V isselected from the group consisting of:

wherein R² and R⁸ are as defined above. In a class of this embodiment,R² is hydrogen. In another class of this third embodiment, V is

In a subclass of this class, R² is hydrogen.

In a fourth embodiment of the compounds of the present invention, R⁸ isselected from the group consisting of:

-   -   —SO₂C₁₋₆ alkyl,    -   —SO₂C₃₋₆ cycloalkyl,    -   —SO₂-aryl, and    -   —SO₂-heteroaryl;        wherein alkyl and cycloalkyl are optionally substituted with one        to five fluorines and wherein aryl and heteroaryl are optionally        substituted with one to five substituents independently selected        from the group consisting of hydroxy, halogen, cyano, nitro,        CO₂H, C₁₋₆ alkyloxycarbonyl, C₁₋₆ alkyl, and C₁₋₆ alkoxy,        wherein alkyl and alkoxy are optionally substituted with one to        five fluorines. In a class of this fourth embodiment, R⁸ is        —SO₂C₁₋₆ alkyl or —SO₂C₃₋₆ cycloalkyl, wherein alkyl and        cycloalkyl are optionally substituted with one to five        fluorines.

In a fifth embodiment of the compounds of the present invention, thereare provided compounds of structural formulae Ia and Ib of the indicatedstereochemical configuration having a trans orientation of the Ar andNH₂ substituents on the two stereogenic tetrahydropyran carbon atomsmarked with an *:

wherein Ar and V are as described above.

In a class of this fifth embodiment, there are provided compounds ofstructural formula Ia of the indicated absolute stereochemicalconfiguration having a trans orientation of the Ar and NH₂ substituentson the two stereogenic tetrahydropyran carbon atoms marked with an *:

In a second class of this fifth embodiment, there are provided compoundsof structural formulae Ic and Id of the indicated stereochemicalconfiguration having a trans orientation of the Ar and NH₂ substituents,a trans orientation of the Ar and V substituents and a cis orientationof the NH₂ and V substituents on the three stereogenic tetrahydropyrancarbon atoms marked with an *:

In a subclass of this class, there are provided compounds of structuralformula Ic of the indicated absolute stereochemical configuration havinga trans orientation of the Ar and NH₂ substituents, a trans orientationof the Ar and V substituents and a cis orientation of the NH₂ and Vsubstituents on the three stereogenic tetrahydropyran carbon atomsmarked with an *:

In a subclass of this subclass, V is selected from the group consistingof:

wherein R² and R⁸ are as defined above. In a subclass of this subclass,R² is hydrogen, and R⁸ is —SO₂C₁₋₆ alkyl or —SO₂C₃₋₆ cycloalkyl, whereinalkyl and cycloalkyl are optionally substituted with one to fivefluorines.

In a third class of this fifth embodiment, there are provided compoundsof structural formulae Ie and If of the indicated stereochemicalconfiguration having a trans orientation of the Ar and NH₂ substituents,a cis orientation of the Ar and V substituents and a trans orientationof the NH₂ and V substituents on the three stereogenic tetrahydropyrancarbon atoms marked with an *:

In a subclass of this class, there are provided compounds of structuralformula Ie of the indicated absolute stereochemical configuration havinga trans orientation of the Ar and NH₂ substituents, a cis orientation ofthe Ar and V substituents and a trans orientation of the NH₂ and Vsubstituents on the three stereogenic tetrahydropyran carbon atomsmarked with an *:

In a subclass of this subclass, V is selected from the group consistingof:

wherein R² and R⁸ are as defined above. In a subclass of this subclass,R² is hydrogen, and R⁸ is —SO₂C₁₋₆ alkyl or —SO₂C₃₋₆ cycloalkyl, whereinalkyl and cycloalkyl are optionally substituted with one to fivefluorines.

In a sixth embodiment of the compounds of the present invention, each R²is independently selected from the group consisting of

-   -   hydrogen;    -   C₁₋₆ alkyl, wherein alkyl is optionally substituted with one to        five fluorines; and    -   C₃₋₆ cycloalkyl, wherein cycloalkyl is optionally substituted        with one to three substituents independently selected from        halogen, hydroxy, C₁₋₄ alkyl, and C₁₋₄ alkoxy, wherein alkyl and        alkoxy are optionally substituted with one to five fluorines.

In a class of this sixth embodiment of the compounds of the presentinvention, each R² is independently selected from the group consistingof hydrogen, C₁₋₃ alkyl, trifluoromethyl, 2,2,2-trifluoroethyl, andcyclopropyl. In a subclass of this class, each R² is hydrogen.

Nonlimiting examples of compounds of the present invention that areuseful as dipeptidyl peptidase-IV inhibitors are the followingstructures having the indicated absolute stereochemical configurationsat the three stereogenic tetrahydropyran carbon atoms:

IC₅₀ DPP-4 Inhi- Example bition

1.0 nM

2.5 nM

2.2 nM

1.9 nM

1.6 nM

1.3 nM

1.6 nM

2.6 nMand pharmaceutically acceptable salts thereof.

As used herein the following definitions are applicable.

“Alkyl”, as well as other groups having the prefix “alk”, such as alkoxyand alkanoyl, means carbon chains which may be linear or branched, andcombinations thereof, unless the carbon chain is defined otherwise.Examples of alkyl groups include methyl, ethyl, propyl, isopropyl,butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and thelike. Where the specified number of carbon atoms permits, e.g., fromC₃₋₁₀, the term alkyl also includes cycloalkyl groups, and combinationsof linear or branched alkyl chains combined with cycloalkyl structures.When no number of carbon atoms is specified, C₁₋₆ is intended.

“Cycloalkyl” is a subset of alkyl and means a saturated carbocyclic ringhaving a specified number of carbon atoms. Examples of cycloalkylinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, and the like. A cycloalkyl group generally is monocyclicunless stated otherwise. Cycloalkyl groups are saturated unlessotherwise defined.

The term “alkoxy” refers to straight or branched chain alkoxides of thenumber of carbon atoms specified (e.g., C₁₋₁₀ alkoxy), or any numberwithin this range [i.e., methoxy (MeO—), ethoxy, isopropoxy, etc.].

The term “alkylthio” refers to straight or branched chain alkylsulfidesof the number of carbon atoms specified (e.g., C₁₋₁₀ alkylthio), or anynumber within this range [i.e., methylthio (MeS—), ethylthio,isopropylthio, etc.].

The term “alkylamino” refers to straight or branched alkylamines of thenumber of carbon atoms specified (e.g., C₁₋₆ alkylamino), or any numberwithin this range [i.e., methylamino, ethylamino, isopropylamino,t-butylamino, etc.].

The term “alkylsulfonyl” refers to straight or branched chainalkylsulfones of the number of carbon atoms specified (e.g., C₁₋₆alkylsulfonyl), or any number within this range [i.e., methylsulfonyl(MeSO₂—), ethylsulfonyl, isopropylsulfonyl, etc.].

The term “alkyloxycarbonyl” refers to straight or branched chain estersof a carboxylic acid derivative of the present invention of the numberof carbon atoms specified (e.g., C₁₋₆ alkyloxycarbonyl), or any numberwithin this range [i.e., methyloxycarbonyl (MeOCO—), ethyloxycarbonyl,or butyloxycarbonyl].

“Aryl” means a mono- or polycyclic aromatic ring system containingcarbon ring atoms. The preferred aryls are monocyclic or bicyclic 6-10membered aromatic ring systems. Phenyl and naphthyl are preferred aryls.The most preferred aryl is phenyl.

The term “heterocyclyl” refers to saturated or unsaturated non-aromaticrings or ring systems containing at least one heteroatom selected fromO, S and N, further including the oxidized forms of sulfur, namely SOand SO₂. Examples of heterocycles include tetrahydrofuran (THF),dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, piperazine,piperidine, 1,3-dioxolane, imidazolidine, imidazoline, pyrroline,pyrrolidine, tetrahydropyran, dihydropyran, oxathiolane, dithiolane,1,3-dioxane, 1,3-dithiane, oxathiane, thiomorpholine, pyrrolidinone,oxazolidin-2-one, imidazolidine-2-one, pyridone, and the like.

“Heteroaryl” means an aromatic or partially aromatic heterocycle thatcontains at least one ring heteroatom selected from O, S and N.Heteroaryls also include heteroaryls fused to other kinds of rings, suchas aryls, cycloalkyls and heterocycles that are not aromatic. Examplesof heteroaryl groups include pyrrolyl, isoxazolyl, isothiazolyl,pyrazolyl, pyridinyl, 2-oxo-(1H)-pyridinyl (2-hydroxy-pyridinyl),oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl,pyrimidinyl, pyrazinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl,benzothiadiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl,indazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, cinnolinyl,phthalazinyl, quinazolinyl, naphthyridinyl, carbazolyl, benzodioxolyl,quinoxalinyl, purinyl, furazanyl, isobenzylfuranyl, benzimidazolyl,benzofuranyl, benzothienyl, quinolyl, indolyl, isoquinolyl,dibenzofuranyl, imidazo[1,2-c]pyridinyl,[1,2,4-triazolo][4,3-c]pyridinyl, pyrazolo[1,5-a]pyridinyl,[1,2,4-triazolo][1,5-c]pyridinyl, 2-oxo-1,3-benzoxazolyl,4-oxo-3H-quinazolinyl, 3-oxo-[1,2,4]-triazolo[4,3-a]-2H-pyridinyl,5-oxo-[1,2,4]-4H-oxadiazolyl, 2-oxo-[1,3,4]-3H-oxadiazolyl,2-oxo-1,3-dihydro-2H-imidazolyl, 3-oxo-2,4-dihydro-3H-1,2,4-triazolyl,and the like. For heterocyclyl and heteroaryl groups, rings and ringsystems containing from 3-15 atoms are included, forming 1-3 rings.

“Halogen” refers to fluorine, chlorine, bromine and iodine. Chlorine andfluorine are generally preferred. Fluorine is most preferred when thehalogens are substituted on an alkyl or alkoxy group (e.g. CF₃O andCF₃CH₂O).

The compounds of the present invention contain one or more asymmetriccenters and can thus occur as racemates, racemic mixtures, singleenantiomers, diastereomeric mixtures, and individual diastereomers. Inparticular the compounds of the present invention have an asymmetriccenter at the stereogenic carbon atoms marked with an * in formulae Ia,Ib, Ic, Id, Ie, and If. Additional asymmetric centers may be presentdepending upon the nature of the various substituents on the molecule.Each such asymmetric center will independently produce two opticalisomers and it is intended that all of the possible optical isomers anddiastereomers in mixtures and as pure or partially purified compoundsare included within the ambit of this invention. The present inventionis meant to comprehend all such isomeric forms of these compounds.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

Some of the compounds described herein may exist as tautomers, whichhave different points of attachment of hydrogen accompanied by one ormore double bond shifts. For example, a ketone and its enol form areketo-enol tautomers. The individual tautomers as well as mixturesthereof are encompassed with compounds of the present invention. Anexample of tautomers which are intended to be encompassed within thecompounds of the present invention is illustrated below:

Formula I shows the structure of the class of compounds withoutpreferred stereochemistry. Formulae Ia and Ib show the preferredstereochemistry at the stereogenic carbon atoms to which are attachedthe NH₂ and Ar groups on the tetrahydropyran ring. Formulae Ic and Idshow the preferred stereochemistry at the stereogenic carbon atoms towhich are attached the NH₂, Ar, and V groups on the tetrahydropyranring.

The independent syntheses of these diastereomers or theirchromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the X-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers are isolated. The separation can be carriedout by methods well known in the art, such as the coupling of a racemicmixture of compounds to an enantiomerically pure compound to form adiastereomeric mixture, followed by separation of the individualdiastereomers by standard methods, such as fractional crystallization orchromatography. The coupling reaction is often the formation of saltsusing an enantiomerically pure acid or base. The diasteromericderivatives may then be converted to the pure enantiomers by cleavage ofthe added chiral residue. The racemic mixture of the compounds can alsobe separated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.

Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

In the compounds of generic Formula I, the atoms may exhibit theirnatural isotopic abundances, or one or more of the atoms may beartificially enriched in a particular isotope having the same atomicnumber, but an atomic mass or mass number different from the atomic massor mass number predominantly found in nature. The present invention ismeant to include all suitable isotopic variations of the compounds ofgeneric Formula I. For example, different isotopic forms of hydrogen (H)include protium (¹H) and deuterium (²H). Protium is the predominanthydrogen isotope found in nature. Enriching for deuterium may affordcertain therapeutic advantages, such as increasing in vivo half-life orreducing dosage requirements, or may provide a compound useful as astandard for characterization of biological samples.Isotopically-enriched compounds within generic Formula I can be preparedwithout undue experimentation by conventional techniques well known tothose skilled in the art or by processes analogous to those described inthe Schemes and Examples herein using appropriate isotopically-enrichedreagents and/or intermediates.

It will be understood that, as used herein, references to the compoundsof structural formula I are meant to also include the pharmaceuticallyacceptable salts, and also salts that are not pharmaceuticallyacceptable when they are used as precursors to the free compounds ortheir pharmaceutically acceptable salts or in other syntheticmanipulations.

The compounds of the present invention may be administered in the formof a pharmaceutically acceptable salt. The term “pharmaceuticallyacceptable salt” refers to salts prepared from pharmaceuticallyacceptable non-toxic bases or acids including inorganic or organic basesand inorganic or organic acids. Salts of basic compounds encompassedwithin the term “pharmaceutically acceptable salt” refer to non-toxicsalts of the compounds of this invention which are generally prepared byreacting the free base with a suitable organic or inorganic acid.Representative salts of basic compounds of the present inventioninclude, but are not limited to, the following: acetate,benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,bromide, camsylate, carbonate, chloride, clavulanate, citrate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate,pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate,polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate,tannate, tartrate, teoclate, tosylate, triethiodide and valerate.Furthermore, where the compounds of the invention carry an acidicmoiety, suitable pharmaceutically acceptable salts thereof include, butare not limited to, salts derived from inorganic bases includingaluminum, ammonium, calcium, copper, ferric, ferrous, lithium,magnesium, manganic, mangamous, potassium, sodium, zinc, and the like.Particularly preferred are the ammonium, calcium, magnesium, potassium,and sodium salts. Salts derived from pharmaceutically acceptable organicnon-toxic bases include salts of primary, secondary, and tertiaryamines, cyclic amines, and basic ion-exchange resins, such as arginine,betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

Also, in the case of a carboxylic acid (—COOH) or alcohol group beingpresent in the compounds of the present invention, pharmaceuticallyacceptable esters of carboxylic acid derivatives, such as methyl, ethyl,or pivaloyloxymethyl, or acyl derivatives of alcohols, such as O-acetyl,O-pivaloyl, O-benzoyl, and O-aminoacyl, can be employed. Included arethose esters and acyl groups known in the art for modifying thesolubility or hydrolysis characteristics for use as sustained-release orprodrug formulations.

Solvates, and in particular, the hydrates of the compounds of structuralformula I are included in the present invention as well.

Exemplifying the invention is the use of the compounds disclosed in theExamples and herein.

The subject compounds are useful in a method of inhibiting thedipeptidyl peptidase-IV enzyme in a patient such as a mammal in need ofsuch inhibition comprising the administration of an effective amount ofthe compound. The present invention is directed to the use of thecompounds disclosed herein as inhibitors of dipeptidyl peptidase-IVenzyme activity.

In addition to primates, such as humans, a variety of other mammals canbe treated according to the method of the present invention. Forinstance, mammals including, but not limited to, cows, sheep, goats,horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine,canine, feline, rodent or murine species can be treated. However, themethod can also be practiced in other species, such as avian species(e.g., chickens).

The present invention is further directed to a method for themanufacture of a medicament for inhibiting dipeptidyl peptidase-IVenzyme activity in humans and animals comprising combining a compound ofthe present invention with a pharmaceutically acceptable carrier ordiluent. More particularly, the present invention is directed to the useof a compound of structural formula I in the manufacture of a medicamentfor use in treating a condition selected from the group consisting ofhyperglycemia, Type 2 diabetes, obesity, and a lipid disorder in amammal, wherein the lipid disorder is selected from the group consistingof dyslipidemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, low HDL, and high LDL.

The subject treated in the present methods is generally a mammal,preferably a human being, male or female, in whom inhibition ofdipeptidyl peptidase-IV enzyme activity is desired. The term“therapeutically effective amount” means the amount of the subjectcompound that will elicit the biological or medical response of atissue, system, animal or human that is being sought by the researcher,veterinarian, medical doctor or other clinician.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term inrelation to pharmaceutical composition, is intended to encompass aproduct comprising the active ingredient(s), and the inert ingredient(s)that make up the carrier, as well as any product which results, directlyor indirectly, from combination, complexation or aggregation of any twoor more of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by admixing acompound of the present invention and a pharmaceutically acceptablecarrier. By “pharmaceutically acceptable” it is meant the carrier,diluent or excipient must be compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

The terms “administration of” and or “administering a” compound shouldbe understood to mean providing a compound of the invention or a prodrugof a compound of the invention to the individual in need of treatment.

The utility of the compounds in accordance with the present invention asinhibitors of dipeptidyl peptidase-IV enzyme activity may bedemonstrated by methodology known in the art. Inhibition constants aredetermined as follows. A continuous fluorometric assay is employed withthe substrate Gly-Pro-AMC, which is cleaved by DPP-4 to release thefluorescent AMC leaving group. The kinetic parameters that describe thisreaction are as follows: K_(m)=50 μM; k_(cat)=75 s⁻¹;k_(cat)/K_(m)=1.5×10⁶ M⁻¹. A typical reaction contains approximately 50μM enzyme, 50 μM Gly-Pro-AMC, and buffer (100 mM HEPES, pH 7.5, 0.1mg/ml BSA) in a total reaction volume of 100 μL. Liberation of AMC ismonitored continuously in a 96-well plate fluorometer using anexcitation wavelength of 360 nm and an emission wavelength of 460 nm.Under these conditions, approximately 0.8 μM AMC is produced in 30minutes at 25 degrees C. The enzyme used in these studies was soluble(transmembrane domain and cytoplasmic extension excluded) human proteinproduced in a baculovirus expression system (Bac-To-Bac, Gibco BRL). Thekinetic constants for hydrolysis of Gly-Pro-AMC and GLP-1 were found tobe in accord with literature values for the native enzyme. To measurethe dissociation constants for compounds, solutions of inhibitor in DMSOwere added to reactions containing enzyme and substrate (final DMSOconcentration is 1%). All experiments were conducted at room temperatureusing the standard reaction conditions described above. To determine thedissociation constants (K_(i)), reaction rates were fit by non-linearregression to the Michaelis-Menton equation for competitive inhibition.The errors in reproducing the dissociation constants are typically lessthan two-fold.

The compounds of structural formula (I), particularly the compounds ofExamples 1-17 shown below, had activity in inhibiting the dipeptidylpeptidase-IV enzyme in the aforementioned assays, generally with an IC₅₀of less than about 1 μM, and more typically of less than 0.1 μM. Suchresults are indicative of the intrinsic activity of the compounds of thepresent invention for use as inhibitors the dipeptidyl peptidase-IVenzyme activity.

Dipeptidyl peptidase-IV enzyme (DPP-4) is a cell surface protein thathas been implicated in a wide range of biological functions. It has abroad tissue distribution (intestine, kidney, liver, pancreas, placenta,thymus, spleen, epithelial cells, vascular endothelium, lymphoid andmyeloid cells, serum), and distinct tissue and cell-type expressionlevels. DPP-4 is identical to the T cell activation marker CD26, and itcan cleave a number of immunoregulatory, endocrine, and neurologicalpeptides in vitro. This has suggested a potential role for thispeptidase in a variety of disease processes in humans or other species.

Accordingly, the subject compounds are useful in a method for theprevention or treatment of the following diseases, disorders andconditions.

Type II Diabetes and Related Disorders:

It is well established that the incretins GLP-1 and GIP are rapidlyinactivated in vivo by DPP-4. Studies with DPP-4^((−/−))-deficient miceand preliminary clinical trials indicate that DPP-4 inhibition increasesthe steady state concentrations of GLP-1 and GIP, resulting in improvedglucose tolerance. By analogy to GLP-1 and GIP, it is likely that otherglucagon family peptides involved in glucose regulation are alsoinactivated by DPP-4 (eg. PACAP). Inactivation of these peptides byDPP-4 may also play a role in glucose homeostasis. The DPP-4 inhibitorsof the present invention therefore have utility in the treatment of typeII diabetes and in the treatment and prevention of the numerousconditions that often accompany Type II diabetes, including Syndrome X(also known as Metabolic Syndrome), reactive hypoglycemia, and diabeticdyslipidemia. Obesity, discussed below, is another condition that isoften found with Type II diabetes that may respond to treatment with thecompounds of this invention.

The following diseases, disorders and conditions are related to Type 2diabetes, and therefore may be treated, controlled or in some casesprevented, by treatment with the compounds of this invention: (1)hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4)obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8)hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels,(11) high LDL levels, (12) atherosclerosis and its sequelae, (13)vascular restenosis, (14) irritable bowel syndrome, (15) inflammatorybowel disease, including Crohn's disease and ulcerative colitis, (16)other inflammatory conditions, (17) pancreatitis, (18) abdominalobesity, (19) neurodegenerative disease, (20) retinopathy, (21)nephropathy, (22) neuropathy, (23) Syndrome X, (24) ovarianhyperandrogenism (polycystic ovarian syndrome), and other disorderswhere insulin resistance is a component. In Syndrome X, also known asMetabolic Syndrome, obesity is thought to promote insulin resistance,diabetes, dyslipidemia, hypertension, and increased cardiovascular risk.Therefore, DPP-4 inhibitors may also be useful to treat hypertensionassociated with this condition.

Obesity:

DPP-4 inhibitors may be useful for the treatment of obesity. This isbased on the observed inhibitory effects on food intake and gastricemptying of GLP-1 and GLP-2. Exogenous administration of GLP-1 in humanssignificantly decreases food intake and slows gastric emptying (Am. J.Physiol., 277: R910-R916 (1999)). ICV administration of GLP-1 in ratsand mice also has profound effects on food intake (Nature Medicine, 2:1254-1258 (1996)). This inhibition of feeding is not observed inGLP-1R^((−/−)) mice, indicating that these effects are mediated throughbrain GLP-1 receptors. By analogy to GLP-1, it is likely that GLP-2 isalso regulated by DPP-4. ICV administration of GLP-2 also inhibits foodintake, analogous to the effects observed with GLP-1 (Nature Medicine,6: 802-807 (2000)). In addition, studies with DPP-4 deficient micesuggest that these animals are resistant to diet-induced obesity andassociated pathology (e.g. hyperinsulinonemia).

Cardiovascular Disease:

GLP-1 has been shown to be beneficial when administered to patientsfollowing acute myocardial infarction, leading to improved leftventricular function and reduced mortality after primary angioplasty(Circulation, 109: 962-965 (2004)). GLP-1 administration is also usefulfor the treatment of left ventricular systolic dysfunction in dogs withdilated cardiomyopathy and ischemic induced left ventriculardysfunction, and thus may prove useful for the treatment of patientswith heart failure (US2004/0097411). DPP-4 inhibitors are expected toshow similar effects through their ability to stabilize endogenousGLP-1.

Growth Hormone Deficiency:

DPP-4 inhibition may be useful for the treatment of growth hormonedeficiency, based on the hypothesis that growth-hormone releasing factor(GRF), a peptide that stimulates release of growth hormone from theanterior pituitary, is cleaved by the DPP-4 enzyme in vivo (WO00/56297). The following data provide evidence that GRF is an endogenoussubstrate: (1) GRF is efficiently cleaved in vitro to generate theinactive product GRF[3-44] (BBA 1122: 147-153 (1992)); (2) GRF israpidly degraded in plasma to GRF[3-44]; this is prevented by the DPP-4inhibitor diprotin A; and (3) GRF[3-44] is found in the plasma of ahuman GRF transgenic pig (J. Clin. Invest., 83: 1533-1540 (1989)). ThusDPP-4 inhibitors may be useful for the same spectrum of indicationswhich have been considered for growth hormone secretagogues.

Intestinal Injury:

The potential for using DPP-4 inhibitors for the treatment of intestinalinjury is suggested by the results of studies indicating thatglucagon-like peptide-2 (GLP-2), a likely endogenous substrate forDPP-4, may exhibit trophic effects on the intestinal epithelium(Regulatory Peptides, 90: 27-32 (2000)). Administration of GLP-2 resultsin increased small bowel mass in rodents and attenuates intestinalinjury in rodent models of colitis and enteritis.

Immunosuppression:

DPP-4 inhibition may be useful for modulation of the immune response,based upon studies implicating the DPP-4 enzyme in T cell activation andin chemokine processing, and efficacy of DPP-4 inhibitors in in vivomodels of disease. DPP-4 has been shown to be identical to CD26, a cellsurface marker for activated immune cells. The expression of CD26 isregulated by the differentiation and activation status of immune cells.It is generally accepted that CD26 functions as a co-stimulatorymolecule in in vitro models of T cell activation. A number of chemokinescontain proline in the penultimate position, presumably to protect themfrom degradation by non-specific aminopeptidases. Many of these havebeen shown to be processed in vitro by DPP-4. In several cases (RANTES,LD78-beta, MDC, eotaxin, SDF-1 alpha), cleavage results in an alteredactivity in chemotaxis and signaling assays. Receptor selectivity alsoappears to be modified in some cases (RANTES). Multiple N-terminallytruncated forms of a number of chemokines have been identified in invitro cell culture systems, including the predicted products of DPP-4hydrolysis.

DPP-4 inhibitors have been shown to be efficacious immunosuppressants inanimal models of transplantation and arthritis. Prodipine(Pro-Pro-diphenyl-phosphonate), an irreversible inhibitor of DPP-4, wasshown to double cardiac allograft survival in rats from day 7 to day 14(Transplantation, 63: 1495-1500 (1997)). DPP-4 inhibitors have beentested in collagen and alkyldiamine-induced arthritis in rats and showeda statistically significant attenuation of hind paw swelling in thismodel [Int. J. Immunopharmacology, 19:15-24 (1997) andImmunopharmacology, 40: 21-26 (1998)]. DPP-4 is upregulated in a numberof autoimmune diseases including rheumatoid arthritis, multiplesclerosis, Graves' disease, and Hashimoto's thyroiditis (ImmunologyToday, 20: 367-375 (1999)).

HIV Infection:

DPP-4 inhibition may be useful for the treatment or prevention of HIVinfection or AIDS because a number of chemokines which inhibit HIV cellentry are potential substrates for DPP-4 (Immunology Today 20: 367-375(1999)). In the case of SDF-1alpha, cleavage decreases antiviralactivity (PNAS, 95: 6331-6 (1998)). Thus, stabilization of SDF-1alphathrough inhibition of DPP-4 would be expected to decrease HIVinfectivity.

Hematopoiesis:

DPP-4 inhibition may be useful for the treatment or prevention ofhematopiesis because DPP-4 may be involved in hematopoiesis. A DPP-4inhibitor, Val-Boro-Pro, stimulated hematopoiesis in a mouse model ofcyclophosphamide-induced neutropenia (WO 99/56753).

Neuronal Disorders:

DPP-4 inhibition may be useful for the treatment or prevention ofvarious neuronal or psychiatric disorders because a number of peptidesimplicated in a variety of neuronal processes are cleaved in vitro byDPP-4. A DPP-4 inhibitor thus may have a therapeutic benefit in thetreatment of neuronal disorders. Endomorphin-2, beta-casomorphin, andsubstance P have all been shown to be in vitro substrates for DPP-4. Inall cases, in vitro cleavage is highly efficient, with k_(cat)/K_(m)about 10⁶ M⁻¹s⁻¹ or greater. In an electric shock jump test model ofanalgesia in rats, a DPP-4 inhibitor showed a significant effect thatwas independent of the presence of exogenous endomorphin-2 (BrainResearch, 815: 278-286 (1999)). Neuroprotective and neuroregenerativeeffects of DPP-4 inhibitors were also evidenced by the inhibitors'ability to protect motor neurons from excitotoxic cell death, to protectstriatal innervation of dopaminergic neurons when administeredconcurrently with MPTP, and to promote recovery of striatal innervationdensity when given in a therapeutic manner following MPTP treatment [seeYong-Q. Wu, et al., “Neuroprotective Effects of Inhibitors of Dipeptidylpeptidase-IV In Vitro and In Vivo,” Int. Conf. On DipeptidylAminopeptidases: Basic Science and Clinical Applications, Sep. 26-29,2002 (Berlin, Germany)].

Anxiety:

Rats naturally deficient in DPP-4 have an anxiolytic phenotype (WO02/34243; Karl et al., Physiol. Behav. 2003). DPP-4 deficient mice alsohave an anxiolytic phenotype using the porsolt and light/dark models.Thus DPP-4 inhibitors may prove useful for treating anxiety and relateddisorders.

Memory and Cognition:

GLP-1 agonists are active in models of learning (passive avoidance,Morris water maze) and neuronal injury (kainate-induced neuronalapoptosis) as demonstrated by During et al. (Nature Med. 9: 1173-1179(2003)). The results suggest a physiological role for GLP-1 in learningand neuroprotection. Stabilization of GLP-1 by DPP-4 inhibitors areexpected to show similar effects

Myocardial Infarction:

GLP-1 has been shown to be beneficial when administered to patientsfollowing acute myocardial infarction (Circulation, 109: 962-965(2004)). DPP-4 inhibitors are expected to show similar effects throughtheir ability to stabilize endogenous GLP-1.

Tumor Invasion and Metastasis:

DPP-4 inhibition may be useful for the treatment or prevention of tumorinvasion and metastasis because an increase or decrease in expression ofseveral ectopeptidases including DPP-4 has been observed during thetransformation of normal cells to a malignant phenotype (J. Exp. Med.,190: 301-305 (1999)). Up- or down-regulation of these proteins appearsto be tissue and cell-type specific. For example, increased CD26/DPP-4expression has been observed on T cell lymphoma, T cell acutelymphoblastic leukemia, cell-derived thyroid carcinomas, basal cellcarcinomas, and breast carcinomas. Thus, DPP-4 inhibitors may haveutility in the treatment of such carcinomas.

Benign Prostatic Hypertrophy:

DPP-4 inhibition may be useful for the treatment of benign prostatichypertrophy because increased DPP-4 activity was noted in prostatetissue from patients with BPH (Eur. J. Clin. Chem. Clin. Biochem., 30:333-338 (1992)).

Sperm Motility/Male Contraception:

DPP-4 inhibition may be useful for the altering sperm motility and formale contraception because in seminal fluid, prostatosomes, prostatederived organelles important for sperm motility, possess very highlevels of DPP-4 activity (Eur. J. Clin. Chem. Clin. Biochem., 30:333-338 (1992)).

Gingivitis:

DPP-4 inhibition may be useful for the treatment of gingivitis becauseDPP-4 activity was found in gingival crevicular fluid and in somestudies correlated with periodontal disease severity (Arch. Oral Biol.,37: 167-173 (1992)).

Osteoporosis:

DPP-4 inhibition may be useful for the treatment or prevention ofosteoporosis because GIP receptors are present in osteoblasts.

Stem Cell Transplantation:

Inhibition of DPP-4 on donor stem cells has been shown to lead to anenhancement of their bone marrow homing efficiency and engraftment, andan increase in survival in mice (Christopherson, et al., Science,305:1000-1003 (2004)). Thus DPP-4 inhibitors may be useful in bonemarrow transplantation.

The compounds of the present invention have utility in treating orpreventing one or more of the following conditions or diseases: (1)hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4)obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8)hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels,(11) high LDL levels, (12) atherosclerosis and its sequelae, (13)vascular restenosis, (14) irritable bowel syndrome, (15) inflammatorybowel disease, including Crohn's disease and ulcerative colitis, (16)other inflammatory conditions, (17) pancreatitis, (18) abdominalobesity, (19) neurodegenerative disease, (20) retinopathy, (21)nephropathy, (22) neuropathy, (23) Syndrome X, (24) ovarianhyperandrogenism (polycystic ovarian syndrome), (25) Type 2 diabetes,(26) growth hormone deficiency, (27) neutropenia, (28) neuronaldisorders, (29) tumor metastasis, (30) benign prostatic hypertrophy,(32) gingivitis, (33) hypertension, (34) osteoporosis, (35) anxiety,(36) memory deficit, (37) cognition deficit, (38) stroke, (39)Alzheimer's disease, and other conditions that may be treated orprevented by inhibition of DPP-4.

The compounds of the present invention are further useful in methods forthe prevention or treatment of the aforementioned diseases, disordersand conditions in combination with other therapeutic agents.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment, prevention, suppression oramelioration of diseases or conditions for which compounds of Formula Ior the other drugs may have utility, where the combination of the drugstogether are safer or more effective than either drug alone. Such otherdrug(s) may be administered, by a route and in an amount commonly usedtherefor, contemporaneously or sequentially with a compound of FormulaI. When a compound of Formula I is used contemporaneously with one ormore other drugs, a pharmaceutical composition in unit dosage formcontaining such other drugs and the compound of Formula I is preferred,particularly in combination with a pharmaceutically acceptable carrier.However, the combination therapy may also include therapies in which thecompound of Formula I and one or more other drugs are administered ondifferent overlapping schedules. It is also contemplated that when usedin combination with one or more other active ingredients, the compoundsof the present invention and the other active ingredients may be used inlower doses than when each is used singly. Accordingly, thepharmaceutical compositions of the present invention include those thatcontain one or more other active ingredients, in addition to a compoundof Formula I.

When a compound of the present invention is used contemporaneously withone or more other drugs, a pharmaceutical composition containing suchother drugs in addition to the compound of the present invention ispreferred. Accordingly, the pharmaceutical compositions of the presentinvention include those that also contain one or more other activeingredients, in addition to a compound of the present invention.

The weight ratio of the compound of the present invention to the secondactive ingredient may be varied and will depend upon the effective doseof each ingredient. Generally, an effective dose of each will be used.Thus, for example, when a compound of the present invention is combinedwith another agent, the weight ratio of the compound of the presentinvention to the other agent will generally range from about 1000:1 toabout 1:1000, preferably about 200:1 to about 1:200. Combinations of acompound of the present invention and other active ingredients willgenerally also be within the aforementioned range, but in each case, aneffective dose of each active ingredient should be used.

In such combinations the compound of the present invention and otheractive agents may be administered separately or in conjunction. Inaddition, the administration of one element may be prior to, concurrentto, or subsequent to the administration of other agent(s).

Examples of other active ingredients that may be administered incombination with a compound of Formula I, and either administeredseparately or in the same pharmaceutical composition, include, but arenot limited to:

(1) insulin sensitizers, including (i) PPARγ agonists, such as theglitazones (e.g. pioglitazone, rosiglitazone, netoglitazone,rivoglitazone, and balaglitazone) and other PPAR ligands, including (1)PPARα/γ □dual agonists, such as muraglitazar, aleglitazar,sodelglitazar, and naveglitazar, (2) PPARα agonists, such as fenofibricacid derivatives (gemfibrozil, clofibrate, ciprofibrate, fenofibrate andbezafibrate), (3) selective PPARγ modulators (SPPARγM's), such as thosedisclosed in WO 02/060388, WO 02/08188, WO 2004/019869, WO 2004/020409,WO 2004/020408, and WO 2004/066963, and (4) PPARγ □partial agonists;(ii) biguanides, such as metformin and its pharmaceutically acceptablesalts, in particular, metformin hydrochloride, and extended-releaseformulations thereof, such as Glumetza®, Fortamet®, and GlucophageXR®;(iii) protein tyrosine phosphatase-1B (PTP-1B) inhibitors;

(2) insulin and insulin analogs or derivatives, such as insulin lispro,insulin detemir, insulin glargine, insulin glulisine, and inhalableformulations of each thereof;

(3) leptin and leptin derivatives, agonists, and analogs, such asmetreleptin;

(4) amylin; amylin analogs, such as davalintide; and amylin agonists,such as pramlintide;

(5) sulfonylurea and non-sulfonylurea insulin secretagogues, such astolbutamide, glyburide, glipizide, glimepiride, mitiglinide, andmeglitinides, such as nateglinide and repaglinide;

(6) α-glucosidase inhibitors (such as acarbose, voglibose and miglitol);

(7) glucagon receptor antagonists, such as those disclosed in WO98/04528, WO 99/01423, WO 00/39088, and WO 00/69810;

(8) incretin mimetics, such as GLP-1, GLP-1 analogs, derivatives, andmimetics (See for example, WO 2008/011446, U.S. Pat. No. 5,545,618, U.S.Pat. No. 6,191,102, and US56583111); and GLP-1 receptor agonists, suchas oxyntomodulin and its analogs and derivatives (See for example, WO2003/022304, WO 2006/134340, WO 2007/100535), glucagon and its analogsand derivatives (See for example, WO 2008/101017), exenatide,liraglutide, taspoglutide, albiglutide, AVE0010, CJC-1134-PC, NN9535,LY2189265, LY2428757, and BIM-51077, including intranasal, transdermal,and once-weekly formulations thereof, such as exenatide QW;

(9) LDL cholesterol lowering agents such as (i) HMG-CoA reductaseinhibitors (lovastatin, simvastatin, pravastatin, cerivastatin,fluvastatin, atorvastatin, pitavastatin, and rosuvastatin), (ii) bileacid sequestering agents (such as cholestyramine, colestimide,colesevelam hydrochloride, colestipol, and dialkylaminoalkyl derivativesof a cross-linked dextran, (iii) inhibitors of cholesterol absorption,such as ezetimibe, and (iv) acyl CoA:cholesterol acyltransferaseinhibitors, such as avasimibe;

(10) HDL-raising drugs, such as niacin or a salt thereof andextended-release versions thereof; MK-524A, which is a combination ofniacin extended-release and the DP-1 antagonist MK-524; and nicotinicacid receptor agonists;

(11) antiobesity compounds;

(12) agents intended for use in inflammatory conditions, such asaspirin, non-steroidal anti-inflammatory drugs (NSAIDs),glucocorticoids, and selective cyclooxygenase-2 (COX-2) inhibitors;

(13) antihypertensive agents, such as ACE inhibitors (such as enalapril,lisinopril, ramipril, captopril, quinapril, and tandolapril), A-IIreceptor blockers (such as losartan, candesartan, irbesartan, olmesartanmedoxomil, valsartan, telmisartan, and eprosartan), renin inhibitors(such as aliskiren), beta blockers (such as and calcium channel blockers(such as;

(14) glucokinase activators (GKAs), such as LY2599506;

(15) inhibitors of 11β-hydroxysteroid dehydrogenase type 1, such asthose disclosed in U.S. Pat. No. 6,730,690; WO 03/104207; and WO04/058741;

(16) inhibitors of cholesteryl ester transfer protein (CETP), such astorcetrapib and MK-0859;

(17) inhibitors of fructose 1,6-bisphosphatase, such as those disclosedin U.S. Pat. Nos. 6,054,587; 6,110,903; 6,284,748; 6,399,782; and6,489,476;

(18) inhibitors of acetyl CoA carboxylase-1 or 2 (ACC1 or ACC2);

(19) AMP-activated Protein Kinase (AMPK) activators;

(20) agonists of the G-protein-coupled receptors: GPR-109, GPR-116,GPR-119, and GPR-40;

(21) SSTR3 antagonists, such as those disclosed in WO 2009/011836;

(22) neuromedin U receptor 1 (NMUR1) and/or neuromedin U receptor 2(NMUR2) agonists, such as those disclosed in WO2007/109135 andWO2009/042053, including, but not limited to, neuromedin U (NMU) andneuromedin S (NMS) and their analogs and derivatives;

(23) inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD);

(24) GPR-105 (P2YR14) antagonists, such as those disclosed in WO2009/000087;

(25) inhibitors of glucose uptake, such as sodium-glucose transporter(SGLT) inhibitors and its various isoforms, such as SGLT-1; SGLT-2, suchas dapagliflozin and remogliflozin; and SGLT-3;

(26) inhibitors of acyl coenzyme A:diacylglycerol acyltransferase 1 and2 (DGAT-1 and DGAT-2);

(27) inhibitors of fatty acid synthase;

(28) inhibitors of acyl coenzyme A:monoacylglycerol acyltransferase 1and 2 (MGAT-1 and MGAT-2);

(29) agonists of the TGR5 receptor (also known as GPBAR1, BG37, GPCR19,GPR131, and M-BAR);

(30) bromocriptine mesylate and rapid-release formulations thereof.;

(31) histamine H3 receptor agonists; and

(32) α2-adrenergic or β3-adrenergic receptor agonists.

Antiobesity compounds that can be combined with compounds of Formula Iinclude topiramate; zonisamide; naltrexone; phentermine; bupropion; thecombination of bupropion and naltrexone; the combination of bupropionand zonisamide; the combination of topiramate and phentermine;fenfluramine; dexfenfluramine; sibutramine; lipase inhibitors, such asorlistat and cetilistat; melanocortin receptor agonists, in particular,melanocortin-4 receptor agonists; CCK-1 agonists; melanin-concentratinghormone (MCH) receptor antagonists; neuropeptide Y₁ or Y₅ antagonists(such as MK-0557); CB1 receptor inverse agonists and antagonists (suchas rimonabant and taranabant); β₃ adrenergic receptor agonists; ghrelinantagonists; bombesin receptor agonists (such as bombesin receptorsubtype-3 agonists); histamine H3 receptor inverse agonists;5-hydroxytryptamine-2c (5-HT2c) agonists, such as lorcaserin; andinhibitors of fatty acid synthase (FAS). For a review of anti-obesitycompounds that can be combined with compounds of the present invention,see S. Chaki et al., “Recent advances in feeding suppressing agents:potential therapeutic strategy for the treatment of obesity,” ExpertOpin. Ther. Patents, 11: 1677-1692 (2001); D. Spanswick and K. Lee,“Emerging antiobesity drugs,” Expert Opin. Emerging Drugs, 8: 217-237(2003); J. A. Fernandez-Lopez, et al., “Pharmacological Approaches forthe Treatment of Obesity,” Drugs, 62: 915-944 (2002); and K. M. Gadde,et al., “Combination pharmaceutical therapies for obesity,” Exp. Opin.Pharmacother., 10: 921-925 (2009).

Glucagon receptor antagonists that can be used in combination with thecompounds of Formula I include, but are not limited to:

-   N-[4-((1S)-1-{3-(3,5-dichlorophenyl)-5-[6-(trifluoromethoxy)-2-naphthyl]-1H-pyrazol-1-yl}ethyl)benzoyl]-β-alanine;-   N-[4-((1R)-1-{3-(3,5-dichlorophenyl)-5-[6-(trifluoromethoxy)-2-naphthyl]-1H-pyrazol-1-yl}ethyl)benzoyl]-β-alanine;-   N-(4-{1-[3-(2,5-dichlorophenyl)-5-(6-methoxy-2-naphthyl)-1H-pyrazol-1-yl]ethyl}benzoyl)-β-alanine;-   N-(4-{(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxy-2-naphthyl)-1H-pyrazol-1-yl]ethyl}benzoyl)-β-alanine;-   N-(4-{(1S)-1-[(R)-(4-chlorophenyl)(7-fluoro-5-methyl-1H-indol-3-yl)methyl]butyl}benzoyl)-β-alanine;    and-   N-(4-{(1S)-1-[(4-chlorophenyl)(6-chloro-8-methylquinolin-4-yl)methyl]butyl}benzoyl)-β-alanine;    and    pharmaceutically acceptable salts thereof.

Inhibitors of stearoyl-coenzyme A delta-9 desaturase (SCD) that can beused in combination with the compounds of Formula I include, but are notlimited to:

-   [5-(5-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,3,4-thiadiazol-2-yl)-2H-tetrazol-2-yl]acetic    acid;-   (2′-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-2,5′-bi-1,3-thiazol-4-yl)acetic    acid;-   (5-{3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]isoxazol-5-yl}-2H-tetrazol-2-yl)acetic    acid;-   (3-{3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,2,4-oxadiazol-5-yl}-1H-pyrrol-1-yl)acetic    acid;-   (5-{5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]pyrazin-2-yl}-2H-tetrazol-2-yl)acetic    acid; and-   (5-{2-[4-(5-bromo-2-chlorophenoxy)piperidin-1-yl]pyrimidin-5-yl}-2H-tetrazol-2-yl)acetic    acid; and    pharmaceutically acceptable salts thereof.

Glucokinase activators that can be used in combination with thecompounds of Formula I include, but are not limited to:

-   3-(6-ethanesulfonylpyridin-3-yloxy)-5-(2-hydroxy-1-methyl-ethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   5-(2-hydroxy-1-methyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   5-(1-hydroxymethyl-propoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-(6-methanesulfonylpyridin-3-yloxy)-5-(1-methoxymethyl-propoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   5-isopropoxy-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   5-(2-fluoro-1-fluoromethyl-ethoxy)-3-(6-methanesulfonylpyridin-3-yloxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide;-   3-({4-[2-(dimethylamino)ethoxy]phenyl}thio)-N-(3-methyl-1,2,4-thiadiazol-5-yl)-6-[(4-methyl-4H-1,2,4-triazol-3-yl)thio]pyridine-2-carboxamide;-   3-({4-[(1-methylazetidin-3-yl)oxy]phenyl}thio)-N-(3-methyl-1,2,4-thiadiazol-5-yl)-6-[(4-methyl-4H-1,2,4-triazol-3-yl)thio]pyridine-2-carboxamide;-   N-(3-methyl-1,2,4-thiadiazol-5-yl)-6-[(4-methyl-4H-1,2,4-triazol-3-yl)thio]-3-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]thio}pyridine-2-carboxamide;    and-   3-[(4-{2R)-[(2R)-2-methylpyrrolidin-1-yl]ethoxy}phenyl)thio-N-(3-methyl-1,2,4-thiadiazol-5-yl)-6-[(4-methyl-4H-1,2,4-triazol-3-yl)thio]pyridine-2-carboxamide;    and pharmaceutically acceptable salts thereof.

Agonists of the GPR-119 receptor that can be used in combination withthe compounds of Formula I include, but are not limited to:

-   rac-cis    5-chloro-2-{4-[2-(2-{[5-(methylsulfonyl)pyridin-2-yl]oxy}ethyl)cyclopropyl]piperidin-1-yl}pyrimidine;-   5-chloro-2-{4-[(1R,2S)-2-(2-{[5-(methylsulfonyl)pyridin-2-yl]oxy}ethyl)cyclopropyl]piperidin-1-yl}pyrimidine;-   rac    cis-5-chloro-2-[4-(2-{2-[4-methylsulfonyl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine;-   5-chloro-2-[4-((1S,2R)-2-{2-[4-(methylsulfonyl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine;-   5-chloro-2-[4-((1R,2S)-2-{2-[4-(methylsulfonyl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine;-   rac    cis-5-chloro-2-[4-(2-{2-[3-(methylsulfonyl)phenoxy]ethyl}cyclopropyl)piperidin-1-yl]pyrimidine;    and-   rac    cis-5-chloro-2-[4-(2-{2-[3-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]ethyl}cyclopropyl)    piperidin-1-yl]pyrimidine; and    pharmaceutically acceptable salts thereof.

Selective PPARγ modulators (SPPARγM's) that can be used in combinationwith the compounds of Formula I include, but are not limited to:

-   (2S)-2-({6-chloro-3-[6-(4-chlorophenoxy)-2-propylpyridin-3-yl]-1,2-benzisoxazol-5-yl}oxy)propanoic    acid;-   (2S)-2-({6-chloro-3-[6-(4-fluorophenoxy)-2-propylpyridin-3-yl]-1,2-benzisoxazol-5-yl}oxy)propanoic    acid;-   (2S)-2-{[6-chloro-3-[6-phenoxy-2-propylpyridin-3-yl]-1,2-benzisoxazol-5-yl]oxy}propanoic    acid;-   (2R)-2-({6-chloro-3-[6-(4-chlorophenoxy)-2-propylpyridin-3-yl]-1,2-benzisoxazol-5-yl}oxy)propanoic    acid;-   (2R)-2-{3-[3-(4-methoxy)benzoyl-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}butanoic    acid;-   (2S)-2-{3-[3-(4-methoxy)benzoyl-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}butanoic    acid;-   2-{3-[3-(4-methoxy)benzoyl-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}-2-methylpropanoic    acid; and-   (2R)-2-{3-[3-(4-chloro)benzoyl-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]phenoxy}propanoic    acid; and    pharmaceutically acceptable salts thereof.

Inhibitors of 11β-hydroxysteroid dehydrogenase type 1 that can be usedin combination with the compounds of Formula I include, but are notlimited to:

-   3-[1-(4-chlorophenyl)-trans-3-fluorocyclobutyl]-4,5-dicyclopropyl-r-4H-1,2,4-triazole;-   3-[1-(4-chlorophenyl)-trans-3-fluorocyclobutyl]-4-cyclopropyl-5-(1-methylcyclopropyl)-r-4H-1,2,4-triazole;-   3-[1-(4-chlorophenyl)-trans-3-fluorocyclobutyl]-4-methyl-5-[2-(trifluoromethoxy)phenyl]-r-4H-1,2,4-triazole;-   3-[1-(4-chlorophenyl)cyclobutyl]-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole;-   3-{4-[3-(ethylsulfonyl)propyl]bicyclo[2.2.2]oct-1-yl}-4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole;-   4-methyl-3-{4-[4-(methylsulfonyl)phenyl]bicyclo[2.2.2]oct-1-yl}-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazole;-   3-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-5-(3,3,3-trifluoropropyl)-1,2,4-oxadiazole;-   3-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-5-(3,3,3-trifluoroethyl)-1,2,4-oxadiazole;-   5-(3,3-difluoro    cyclobutyl)-3-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-1,2,4-oxadiazole;-   5-(1-fluoro-1-methylethyl)-3-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-1,2,4-oxadiazole;-   2-(1,1-difluoroethyl)-5-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-1,3,4-oxadiazole;-   2-(3,3-difluorocyclobutyl)-5-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-1,3,4-oxadiazole;    and-   5-(1,1-difluoroethyl)-3-(4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]oct-1-yl)-1,2,4-oxadiazole;    and    pharmaceutically acceptable salts thereof.

Somatostatin subtype receptor 3 (SSTR3) antagonists that can be used incombination with the compounds of Formula I include, but are not limitedto:

and pharmaceutically acceptable salts thereof.

AMP-activated Protein Kinase (AMPK) activators that can be used incombination with the compounds of Formula I include, but are not limitedto:

and pharmaceutically acceptable salts thereof.

Inhibitors of acetyl-CoA carboxylase-1 and 2 (ACC-1 and ACC-2) that canbe used in combination with the compounds of Formula I include, but arenot limited to:

-   3-{1′-[(1-cyclopropyl-4-methoxy-1H-indol-6-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}benzoic    acid;-   5-{1′-[(1-cyclopropyl-4-methoxy-1H-indol-6-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}nicotinic    acid;-   1′-[(1-cyclopropyl-4-methoxy-1H-indol-6-yl)carbonyl]-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one;-   1′-[(1-cyclopropyl-4-ethoxy-3-methyl-1H-indol-6-yl)carbonyl]-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one;-   5-{1′-[(1-cyclopropyl-4-methoxy-3-methyl-1H-indol-6-yl)carbonyl]-4-oxo-spiro[chroman-2,4′-piperidin]-6-yl}nicotinic    acid;-   4′-({6-(5-carbamoylpyridin-2-yl)-4-oxo    spiro[chroman-2,4′-piperidin]-1′-yl}carbonyl)-2′,6′-diethoxybiphenyl-4-carboxylic    acid;-   2′,6′-diethoxy-4′-{[6-(1-methyl-1H-pyrazol-4-yl)-4-oxospiro[chroman-2,4′-piperidin]-1′-yl]carbonyl}biphenyl-4-carboxylic    acid;-   2′,6′-diethoxy-3-fluoro-4′-{[6-(1-methyl-1H-pyrazol-4-yl)-4-oxospiro[chroman-2,4′-piperidin]-1′-yl]carbonyl}biphenyl-4-carboxylic    acid;-   5-[4-({6-(3-carbamoylphenyl)-4-oxospiro[chroman-2,4′-piperidin]-1′-yl}carbonyl)-2,6-diethoxyphenyl]nicotinic    acid;-   sodium    4′-({6-(5-carbamoylpyridin-2-yl)-4-oxospiro[chroman-2,4′-piperidin]-1′-yl}carbonyl)-2′,6′-diethoxybiphenyl-4-carboxylate;-   methyl    4′-({6-(5-carbamoylpyridin-2-yl)-4-oxospiro[chroman-2,4′-piperidin]-1′-yl}carbonyl)-2′,6′-diethoxybiphenyl-4-carboxylate;-   1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one;-   (5-{1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}-2H-tetrazol-2-yl)methyl    pivalate;-   5-{1′-[(8-cyclopropyl-4-methoxyquinolin-2-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}nicotinic    acid;-   1′-(8-methoxy-4-morpholin-4-yl-2-naphthoyl)-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one;    and-   1′-[(4-ethoxy-8-ethylquinolin-2-yl)carbonyl]-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one;    and    pharmaceutically acceptable salts and esters thereof.

The compounds of the present invention may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. In addition to thetreatment of warm-blooded animals such as mice, rats, horses, cattle,sheep, dogs, cats, monkeys, etc., the compounds of the invention areeffective for use in humans.

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in dosage unit form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active object compound is included inan amount sufficient to produce the desired effect upon the process orcondition of diseases. As used herein, the term “composition” isintended to encompass a product comprising the specified ingredients inthe specified amounts, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example starch, gelatin or acacia, and lubricatingagents, for example magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the techniques described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of the present invention may also be administered in theform of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compounds of the present invention are employed.(For purposes of this application, topical application shall includemouthwashes and gargles.)

The pharmaceutical composition and method of the present invention mayfurther comprise other therapeutically active compounds as noted hereinwhich are usually applied in the treatment of the above mentionedpathological conditions.

In the treatment or prevention of conditions which require inhibition ofdipeptidyl peptidase-IV enzyme activity an appropriate dosage level willgenerally be about 0.01 to 500 mg per kg patient body weight per daywhich can be administered in single or multiple doses. Preferably, thedosage level will be about 0.1 to about 250 mg/kg per day; morepreferably about 0.5 to about 100 mg/kg per day. A suitable dosage levelmay be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day,or about 0.1 to 50 mg/kg per day. Within this range the dosage may be0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration,the compositions are preferably provided in the form of tabletscontaining 1.0 to 1000 mg of the active ingredient, particularly 1.0,5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0,300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 mg of theactive ingredient for the symptomatic adjustment of the dosage to thepatient to be treated. The compounds may be administered on a regimen of1 to 4 times per day, preferably once or twice per day.

When treating or preventing diabetes mellitus and/or hyperglycemia orhypertriglyceridemia or other diseases for which compounds of thepresent invention are indicated, generally satisfactory results areobtained when the compounds of the present invention are administered ata daily dosage of from about 0.1 mg to about 100 mg per kilogram ofanimal body weight, preferably given as a single daily dose or individed doses two to six times a day, or in sustained release form. Formost large mammals, the total daily dosage is from about 1.0 mg to about1000 mg, preferably from about 1 mg to about 50 mg. In the case of a 70kg adult human, the total daily dose will generally be from about 7 mgto about 350 mg. This dosage regimen may be adjusted to provide theoptimal therapeutic response.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

Synthetic methods for preparing the compounds of the present inventionare illustrated in the following Schemes and Examples. Startingmaterials are commercially available or may be made according toprocedures known in the art or as illustrated herein.

The compounds of the present invention can be prepared fromintermediates such as those of formula II and III using standardreductive amination conditions followed by deprotection,

where Ar and V are as defined above and P is a suitable nitrogenprotecting group such as tert-butoxycarbonyl (BOC), benzyloxycarbonyl(Cbz), or 9-fluorenylmethoxycarbonyl (Fmoc). The preparation of theseintermediates is described in the following Schemes.

Intermediates of formula II are known in the literature or may beconveniently prepared by a variety of methods familiar to those skilledin the art. One common route is illustrated in Scheme 1. Substitutedbenzoyl halide 1 is treated with phenol in the presence of a base suchas N,N-diisopropylethylamine to form the ester 2. Treatment of 2 withthe anion generated from nitromethane using sodium hydride gives thenitroketone 3. Alternatively, the nitroketone 3 can be made by reactingaldehyde 1a with nitromethane in the presence of a base and oxidizingthe resulting nitroalcohol 1b with an oxidizing agent such as Jonesreagent. Heating the nitroketone 3 with 3-iodo-2-(iodomethyl)prop-1-enegives the pyran 4, which, when reduced with sodium borohydride andisomerized with a base such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),provides the trans pyran 5. The enantiomers of 5 may be separated atthis stage by a variety of methods known to those skilled in the art.Conveniently, the racemate may be resolved by HPLC using a chiralcolumn. The nitro-substituted pyran 5 is then reduced, for example,using zinc and an acid, such as hydrochloric acid, and the resultingamine 6 protected, for example, as its BOC derivative, by treatment withdi-tert-butyl dicarbonate to give 7. Treatment of 7 with osmiumtetroxide and N-methylmorpholine N-oxide forms the diol 8 which upontreatment with sodium periodate gives intermediate pyranone IIa.

Intermediates of formula III are known in the literature or may beconveniently prepared by a variety of methods familiar to those skilledin the art. One common route to prepare tetrahydropyrrolopyrazole IIIais illustrated in Scheme 2. Trityl- or Boc-protected pyrrolidinol 9 maybe oxidized by a variety of methods, such as the Swern procedure,commonly known to those in the art, to give the ketone 10, which upontreatment and heating with N,N-dimethylformamide dimethyl acetal(DMF-DMA) gives 11. The desired intermediate IIIa may then be readilyobtained by heating a solution of 11 with hydrazine 12 in a suitablesolvent such as ethanol optionally in the presence of a base such assodium ethoxide followed by removal of the protecting group with acid.

As illustrated in Scheme 3, the compounds of the present inventionstructural formula (I) may be prepared by reductive amination ofIntermediate II in the presence of Intermediate III using reagents suchas sodium cyanoborohydride, decaborane, or sodium triacetoxyborohydridein solvents such as dichloromethane, tetrahydrofuran, or methanol toprovide Intermediate IV. The reaction is conducted optionally in thepresence of a Lewis acid such as titanium tetrachloride or titaniumtetraisopropoxide. The reaction may also be facilitated by adding anacid such as acetic acid. In some cases, Intermediate III may be a salt,such as a hydrochloric acid or trifluoroacetic acid salt, and in thesecases it is convenient to add a base, generallyN,N-diisopropylethylamine, to the reaction mixture. The protecting groupis then removed with, for example, trifluoroacetic acid or methanolichydrogen chloride in the case of Boc, or palladium-on-carbon andhydrogen gas in the case of Cbz to give the desired amine I. The productis purified, if necessary, by recrystallization, trituration,preparative thin layer chromatography, flash chromatography on silicagel, such as with a Biotage® apparatus, or HPLC. Compounds that arepurified by HPLC may be isolated as the corresponding salt.

In some cases the product I or synthetic intermediates illustrated inthe above schemes may be further modified, for example, by manipulationof substituents on Ar or V. These manipulations may include, but are notlimited to, reduction, oxidation, alkylation, acylation, and hydrolysisreactions that are commonly known to those skilled in the art. In somecases the order of carrying out the foregoing reaction schemes may bevaried to facilitate the reaction or to avoid unwanted reactionproducts.

The compounds of structural formula I of the present invention can beprepared according to the procedures of the following Schemes andExamples, using appropriate materials and are further exemplified by thefollowing specific examples. The compounds illustrated in the examplesare not, however, to be construed as forming the only genus that isconsidered as the invention. The Examples further illustrate details forthe preparation of the compounds of the present invention. Those skilledin the art will readily understand that known variations of theconditions and processes of the following preparative procedures can beused to prepare these compounds. The instant compounds are generallyisolated in the form of their pharmaceutically acceptable salts, such asthose described previously hereinabove. The free amine basescorresponding to the isolated salts can be generated by neutralizationwith a suitable base, such as aqueous sodium hydrogencarbonate, sodiumcarbonate, sodium hydroxide, and potassium hydroxide, and extraction ofthe liberated amine free base into an organic solvent followed byevaporation. The amine free base isolated in this manner can be furtherconverted into another pharmaceutically acceptable salt by dissolutionin an organic solvent followed by addition of the appropriate acid andsubsequent evaporation, precipitation, or crystallization. Alltemperatures are degrees Celsius unless otherwise noted. Mass spectra(MS) were measured by electron-spray ion-mass spectroscopy.

The following is a list of abbreviations used in the description of thesynthesis of the Intermediates and Examples shown below.

List of Abbreviations:

-   Alk=alkyl-   Ar=aryl-   Boc=tert-butoxycarbonyl-   br=broad-   CH₂Cl₂=dichloromethane-   d=doublet-   DBU=1,8-diazabicyclo[5.4.0]undec-7-ene-   DEAD=diethyl azodicarboxylate-   DMA=N,N-dimethylacetamide-   DMF=dimethylformamide-   DMSO=dimethyl sulfoxide-   ESI=electrospray ionization-   EtOAc=ethyl acetate-   HATU=O-(7-azabenzotriazol-1-yl)-N,N,N,N′-tetramethyluronium    hexafluorophosphate-   HOAc=acetic acid-   LC-MS=liquid chromatography-mass spectroscopy-   LiOH=lithium hydroxide-   m=multiplet-   MeOH=methyl alcohol-   MgSO₄=magnesium sulfate-   MS=mass spectroscopy-   NaOH=sodium hydroxide-   Na₂SO₄=sodium sulfate-   NMR=nuclear magnetic resonance spectroscopy-   PG=protecting group-   Ph=phenyl-   Rt or RT=room temperature-   s=singlet-   t=triplet-   TFA=trifluoroacetic acid-   THF=tetrahydrofuran

INTERMEDIATE 1

tert-Butyl[(2R,3S)-5-oxo-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl]carbamateStep A: Phenyl 2,4,5-trifluorobenzoate

A solution of phenol (13.3 g, 141 mmol) in dry dichloromethane (370 mL)was cooled in ice bath and treated with N,N-diisopropylethylamine (34mL, 193 mmol) followed by dropwise addition of 2,4,5-trifluorobenzoylchloride (25 g, 129 mmol) over a period of 15 minutes. The ice bath wasremoved, stirring was continued for two hours at room temperature andthe solution was then transferred to a separatory funnel and the organiclayer was washed successively with hydrochloric acid solution (2N, 150mL), saturated aqueous sodium bicarbonate solution (150 mL), and brine(150 mL), dried over anhydrous sodium sulfate, filtered, evaporated andthe resulting solid product was purified on silica in portions byeluting successively with hexane, and then 0-5% ether in hexane in agradient fashion to yield phenyl 2,4,5-trifluorobenzoate as white solid.

Step B: 2-Nitro-1-(2,4,5-trifluorophenyl)ethanone

Sodium hydride (12 g, 60% in oil, 297 mmol) was rinsed with hexane(4×100 mL), flushed with anhydrous nitrogen, suspended inN,N-dimethylformamide (350 mL) and then treated with nitromethane (44mL, 81 mmol). The resultant mixture was stirred at room temperature for2.5 hours, cooled to 0° C. and then treated with a solution of phenyl2,4,5-trifluorobenzoate (22.8 g, 90.0 mmol) in N,N-dimethylformamide(180 mL) over a period of two hours. The reaction mixture was kept atthe same temperature overnight and stirring continued for an additionalhour at room temperature. The mixture was poured into ice (400 g) withconc. hydrochloric acid (48 mL). The aqueous mixture was extracted withethyl acetate (3×250 mL). The combined organic layers were washed withbrine (40 mL), dried over anhydrous sodium sulfate, filtered, andevaporated under reduced pressure. The crude product was dissolved inether-hexane (1:1, 240 mL) and water (200 mL). The organic layer wasseparated, and the crystals which formed upon standing and cooling inthe freezer were recovered by filtration and dried to yield2-nitro-1-(2,4,5-trifluorophenyl)ethanone as an off-white solid.

Step C:3-Methylene-5-nitro-6-(2,4,5-trifluorophenyl)-3,4-dihydro-2H-pyran

A mixture of 3-chloro-2-(chloromethyl)prop-1-ene (1.0 g, 8 mmol) andsodium iodide (6.6 g, 44 mmol) in acetone (60 mL) was stirred at roomtemperature for 20 hours, evaporated under reduced pressure anddissolved in dichloromethane (150 mL) and water (50 mL). The organiclayer was dried over sodium sulfate, filtered and evaporated to yield3-iodo-2-(iodomethyl)prop-1-ene as a reddish oil (2.45 g).N,N-diisopropylethylamine (0.20 mL) was added to a solution of2-nitro-1-(2,4,5-trifluorophenyl)ethanone (110 mg, 0.5 mmol) inN,N-dimethylformamide (3 mL) and 3-iodo-2-(iodomethyl)prop-1-ene (170mg, 0.55 mmol) and the mixture was heated at 60° C. for 2.5 hours,evaporated and purified by chromatography on a Biotage Horizon® system(silica, gradient 0-30% dichloromethane in hexane) to yield3-methylene-5-nitro-6-(2,4,5-trifluorophenyl)-3,4-dihydro-2H-pyran.

Step D:(2R,3S)-5-Methylene-3-nitro-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran

To a solution of3-methylene-5-nitro-6-(2,4,5-trifluorophenyl)-3,4-dihydro-2H-pyran (798mg, 2.94 mmol) in chloroform (42 mL) and isopropyl alcohol (7.8 mL) wasadded silica gel (5.1 g), and sodium borohydride (420 mg, 11.1 mmol),and the reaction mixture stirred for 30 minutes at room temperature. Thereaction mixture was then quenched by dropwise addition of hydrochloricacid (6 mL, 2N) and filtered. The resulting solid residue was washedwith ethyl acetate (100 mL). The combined filtrate was washedsuccessively with saturated aqueous sodium bicarbonate solution andbrine, dried over anhydrous sodium sulfate, and evaporated. Theresultant amber oil (802 mg) was dissolved in tetrahydrofuran (15 mL)and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 40 μl) was added. Thesolution was stirred for 105 minutes and then transferred to aseparatory funnel containing ethyl acetate (100 mL) and 1N hydrochloricacid (50 mL). The organic layer was washed with brine and the aqueouslayer extracted with ethyl acetate. The combined organic layer was driedover anhydrous sodium sulfate, filtered and evaporated to yield a crudeproduct which was purified by flash chromatography (silica, 8-10% etherin hexane) to yield trans-5-methylene-3-nitro-2-(2,4,5trifluorophenyl)tetrahydro-2H-pyran. A portion of this product (388 mg)was resolved by HPLC (ChiralCel OD, 1.5% isopropyl alcohol in heptane)to yield the slower-moving enantiomer,(2R,3S)-5-methylene-3-nitro-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran.

Step E:(2R,3S)-5-Methylene-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-amine

To a vigorously stirred suspension of(2R,3S)-5-methylene-3-nitro-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran(200 mg, 0.73 mmol) and zinc powder (561 mg, 8.59 mmol) in ethanol (7mL) was added 6N hydrochloric acid (2.3 mL, 14 mmol). After one hour,the mixture was treated with ether (100 mL) and aqueous sodium hydroxidesolution (2.5N, 40 mL). The organic layer was washed with saturatedbrine, dried over anhydrous sodium sulfate and evaporated to yield(2R,3S)-5-methylene-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-aminewhich was used in the next step without further purification.

Step F:tert-Butyl[(2R,3S)-5-methylene-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl]carbamate

To a solution of(2R,3S)-5-methylene-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-amine(177 mg, 0.73 mmol) in dichloromethane (5 mL) was added di-tert-butyldicarbonate (239 mg, 1.1 mmol) and the mixture stirred for 2.5 hours atroom temperature. The solution was evaporated under reduced pressure togivetert-butyl[(2R,3S)-5-methylene-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl]carbamateas a white solid. It was used in the next step without furtherpurification.

Step G:tert-Butyl[(2R,3S)-5-hydroxy-5-(hydroxymethyl)-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl]carbamate

To a solution oftert-butyl[(2R,3S)-5-methylene-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl]carbamate(203 mg, 0.59 mmol) in tert-butyl alcohol (6 mL), acetone (3 mL) andwater (1.5 mL) was added osmium tetroxide (0.113 mL of 2.5% solution intert-butyl alcohol, 0.009 mmol). The resultant mixture was stirred atroom temperature for 10 minutes and then treated with N-methylmorpholineN-oxide (92 mg, 0.79 mmol) and stirred. After two days, the reactionmixture was treated with aqueous sodium bisulfite solution (5 mL, 2.0/V)followed after 10 min by ethyl acetate. The organic layer was washedsuccessively with 2N hydrochloric acid and saturated aqueous sodiumbicarbonate solution, dried over anhydrous sodium sulfate, filtered andevaporated to yield tert-butyl[(2R,3S)-5-hydroxy-5-(hydroxymethyl)-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl]carbamatewhich was used in the next step without further purification.

Step H:tert-Butyl[(2R,3S)-5-oxo-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl]carbamate

To a solution oftert-butyl[(2R,3S)-5-hydroxy-5-(hydroxymethyl)-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl]carbamate(223 mg, 0.59 mmol) in tetrahydrofuran (4 mL) was added a solution ofsodium periodate (143 mg, 0.67 mmol) in water (1.3 mL) and the mixturestirred for 3 hours. The mixture was concentrated and purified by flashchromatography (silica, gradient 5-20% ethyl acetate in chloroform) toyieldtert-butyl[(2R,3S)-5-oxo-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl]carbamateas white solid.

INTERMEDIATE 2

tert-Butyl[(2R,3S)-5-oxo-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl]carbamateStep A: 1-(2,5-Difluorophenyl)-2-nitroethanol

To sodium hydroxide (1N, 3 L) and methanol (1500 mL) at 5° C. was addeda solution of 2,5-difluorobenzaldehyde (350 g, 2.46 mol) andnitromethane (157 mL, 2.9 mol) in methanol (350 mL) dropwise over aperiod of 1 h. The reaction mixture was then neutralized with glacialacetic acid (165 mL). Diethyl ether (1500 mL) was added and the layersseparated. The organic layer was washed successively with saturatedaqueous sodium carbonate solution (1000 mL), and saturated aqueous brine(1000 mL). The organic layer was dried over anhydrous magnesium sulfate,filtered and concentrated to afford1-(2,5-difluorophenyl)-2-nitroethanol that was used without furtherpurification in Step B.

Step B: 2-Nitro-1-(2,5-difluorophenyl)ethanone

A solution of Dess-Martin periodinane (125 g) in dichloromethane (600mL) was added to a solution of the nitroalcohol made in Step A (46.3 g)at 10° C. over a period of 30 min. Stirring was continued for 2 h, andthe reaction mixture was then poured onto a mixture of sodiumbicarbonate (300 g) and sodium thiosulfate (333 g) in water (3 L). Thedesired product was extracted with methyl t-butyl ether (MTBE) (2 L).The aqueous layer was neutralized with HCl (2N, 1.5 L) and extractedwith MTBE (3 L). The combined organic layers were dried over anhydrousmagnesium sulfate, filtered, evaporated and the residue was purified bychromatography (silica gel, eluting with dichloromethane) to yield thedesired nitroketone.

Step C: 3-Iodo-2-(iodomethyl)prop-1-ene

A mixture of 3-chloro-2-(chloromethyl)prop-1-ene (1.0 g, 8 mmol) andsodium iodide (6.6 g, 44 mmol) in acetone (60 mL) was stirred at roomtemperature for 20 h, evaporated under reduced pressure and partitionedbetween dichloromethane (150 mL) and water (50 mL). The organic layerwas dried over sodium sulfate, filtered and evaporated to yield3-iodo-2-(iodomethyl)prop-1-ene as a reddish oil.

Step D: 3-Methylene-5-nitro-6-(2,5-difluorophenyl)-3,4-dihydro-2H-pyran

N,N-diisopropylethylamine (184 mL) was added to a solution of2-nitro-1-(2,5-difluorophenyl)ethanone (92.7 g, 461 mmol) inN,N-dimethylformamide (1000 mL) and 3-iodo-2-(iodomethyl)prop-1-ene (156g, 507 mmol). The mixture was heated at 60° C. for 2 h, evaporated andpurified by chromatography (silica gel, gradient 0-30% dichloromethanein hexane) to yield3-methylene-5-nitro-6-(2,5-difluorophenyl)-3,4-dihydro-2H-pyran.

Step E:(2R,3S)-5-Methylene-3-nitro-2-(2,5-difluorophenyl)tetrahydro-2H-pyran

This compound was made by following the same method described inIntermediate 1, Step D by using3-methylene-5-nitro-6-(2,5-trifluorophenyl)-3,4-dihydro-2H-pyran.

Step F:(2R,3S)-5-Methylene-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine

This compound was made by following the same method described inIntermediate 1, Step E by using(2R,3S)-5-Methylene-3-nitro-2-(2,5-difluorophenyl)tetrahydro-2H-pyran.

Step G:tert-Butyl[(2R,3S)-5-methylene-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl]carbamate

This compound was made by following the same method described inIntermediate 1, Step F by using(2R,3S)-5-methylene-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine.

Step H:tert-Butyl[(2R,3S)-5-hydroxy-5-(hydroxymethyl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl]carbamate

This compound was made by following the same method described inIntermediate 1, Step G by usingtert-butyl[(2R,3S)-5-methylene-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl]carbamate.

Step I:tert-Butyl[(2R,3S)-5-oxo-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl]carbamate

To a solution oftert-butyl[(2R,3S)-5-hydroxy-5-(hydroxymethyl)-2-(2,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl]carbamate(10.5 g) in methanol (100 mL) at 0° C. was added pyridine (7.8 mL) andlead tetraacetate (21.7 g). The reaction mixture was stirred for 20 min.Aqueous work-up with ethyl acetate gave crude product which was purifiedby chromatography (silica, 0-50% ethyl acetate/heptane) to yieldtert-butyl[(2R,3S)-5-oxo-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl]carbamateas white solid.

INTERMEDIATE 3

Step A: tert-Butyl(3Z)-3-[(dimethylamino)methylene]-4-oxopyrrolidine-1-carboxylate

A solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (40 g, 216 mmol)was treated with DMF-DMA (267 g, 2241 mmol) and heated at 105° C. for 40min. The solution was cooled and evaporated under reduced pressure andthe resulting orange solid was treated with hexane (200 mL) and cooledin a refrigerator for 3 days. The resulting brownish-yellow solidobtained as such was collected by filtration, dried and used in the nextstep without further purification.

Step B: 1,4,5,6-Tetrahydropyrrolo[3,4-c]pyrazole

A solution of hydrazine (3 mL) and tert-butyl(3Z)-3-[(dimethylamino)methylene]-4-oxopyrrolidine-1-carboxylate (19.22g) in ethanol (40 mL) was heated at 85° C. in a sealed tube for 4 h.Solvent was removed under reduced pressure, and the residue wastriturated with dichloromethane (160 mL) and ethyl acetate (15 mL). Theresulting solid was filtered. The filtrate was concentrated and theresulting solid was triturated again and filtered. The combined solidswere treated with 4N hydrochloric acid (250 mL) in methanol and stirredfor 6 h. The reaction mixture was concentrated and dried. The resultingsolid was treated again for 6 h with 4N hydrochloric acid (250 mL) inmethanol. After concentration and drying, the resulting hydrochloridesalt was treated with ammonia in methanol (2N, 300 mL) and ammoniumhydroxide solution in water (28%, 30 mL) and concentrated to dryness.The solid obtained was treated with methanol (70 mL) and water (5 mL)and purified in three batches on Biotage Horizon® system (silica,gradient 5-17% methanol containing 10% concentrated ammonium hydroxidein ethyl acetate) to yield 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole. ¹HNMR (500 MHz, CD₃OD): δ 4.04 (d, 4H); 7.39 (s, 1H).

INTERMEDIATE 41-(Cyclopentylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole2-(Cyclopentylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole

Step A: tert-Butyl1-(cyclopentylsulfonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate(A) and tert-butyl2-(cyclopentylsulfonyl)-2,6-dihydropyrrolo[3,4-e]pyrazole-5(4H)-carboxylate(B)

To a solution of N-Boc-pyrazolopyrrolidine (Intermediate 3, Step B) (316mg, 1.51 mmol) in dichloromethane was added N,N-diisopropylethylamine(0.791 mL) followed by cyclopentanesulfonyl chloride (0.299 mL, 2.265mmol). The mixture was stirred at room temperature for 18 h. Thereaction mixture was loaded on Biotage™ column and chromatographed with50% ethyl acetate in hexane to give intermediates A and B both asoff-white solids. LC-MS: 342.09 (M+1).

Step B: 1-(Cyclopentylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole

Intermediate A prepared in the previous step (84 mg) in dichloromethane(4.0 mL) was treated with trifluoroacetic acid (4.0 mL) at roomtemperature for 2 h. The reaction mixture was concentrated and purifiedon Biotage™ column eluting with 2.5-5% methanol and 0.25-0.5% ammoniumhydroxide in dichloromethane to afford the title compound as brownsyrup. ¹H NMR (500 MHz, CD₃OD): δ 1.60-1.81 (m, 4H); 1.92-2.11 (m, 4H);3.92 (m, 2H); 4.05 (m, 1H); 4.12 (m, 2H); and 7.60 (s, 1H). LC-MS:242.10 (M+1).

2-(Cyclopentylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-e]pyrazole

Intermediate B prepared in Step A above (275 mg) in dichloromethane (4.0mL) was treated with trifluoroacetic acid (4.0 mL) at room temperaturefor 2 h. The reaction was concentrated and the residue was purified onsilica gel column eluting with 5% methanol and 0.5% ammonium hydroxidein dichloromethane to produce the title compound as brown syrup. ¹H NMR(500 MHz, CD₃OD): δ 1.60-1.75 (m, 4H); 1.89-2.07 (m, 4H); 3.93-4.01 (m,5H); and 7.84 (s, 1H). LC-MS: 242.05 (M+1).

INTERMEDIATE 5

2-(Methylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole Step A:tert-Butyl1-(methylsulfonyl)]-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate(A) and tert-butyl2-(methylsulfonyl)]-2,6-dihydropyrrolo[3,4-e]pyrazole-5(4H)-carboxylate(B)

A suspension of N-Boc-pyrazolopyrrolidine (Intermediate 3, Step B)(27.16 g, 130 mmol) in anhydrous acetonitrile (1.0 L) was charged in a2.0 L three-neck flask fitted with a thermometer and an addition funneland then treated with sodium hydride (60% dispersion in oil, 6.23 g, 156mmol) while under nitrogen atmosphere in one portion. The reactionmixture was stirred at room temperature for 2 h. The resulting whitesuspension was then cooled in an ice bath and methanesulfonyl chloride(25.2 mL, 324 mmol) was slowly added via addition funnel. The ice bathwas then removed and the mixture was stirred 1 h at room temperature.The reaction mixture was quenched with water (500 mL) and the layerswere separated. The aqueous layer was then extracted with 2×500 mL ofdichloromethane. The combined organic layers were dried over sodiumsulfate and concentrated under reduced pressure to give a mixture ofproducts A and B as colorless syrups. NMR in CD₃OD indicated a 1:1mixture of two products, in which the proton on the pyrazole ring inproduct A appeared at 7.70 ppm while the proton in product B appeared at7.95 pm. LC-MS: 288.08 (M+1).

Step B: 2-(Methylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole

Trifluoroacetic acid (200 mL) was added slowly to a solution containingintermediates A and B prepared in the previous step (48.4 g, 168 mmol)in dichloromethane (400 mL) at 0° C. After addition, the cooling bathwas removed and the reaction was allowed to stir at room temperature for2 h. Solvent was removed under reduced pressure and the resultingtrifluoroacetate salt was then neutralized with 500 mL of 25% methanoland 2.5% ammonium hydroxide in dichloromethane. After removal ofsolvent, the desired Intermediate 5 was obtained after chromatography ona Biotage™ column (2×340 g) eluting with 2.5-12.5% methanol and0.25-1.25% ammonium hydroxide in dichloromethane. LC-MS: 109.85 (M+1).

INTERMEDIATE 61-(Cyclopropylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole2-(Cyclopropylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole

Step A: tert-Butyl1-(cyclopropylsulfonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate(A) and tert-butyl2-(cyclopentylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate(B)

A suspension of sodium hydride (60% dispersion in oil, 1.55 g, 38.7mmol) in anhydrous acetonitrile (200 mL) was added toN-Boc-pyrazolopyrrolidine (Intermediate 3, Step B) (5.3 g, 25.5 mmol) inone portion under nitrogen at room temperature. The reaction mixture wasstirred at room temperature for 2 h. To the resulting white suspensionwas slowly added cyclopropanesulfonyl chloride (6.9 g, 49.1 mmol) andthe mixture was stirred at room temperature for 18 h, quenched withwater (120 mL) and the layers were separated. The aqueous layer was thenextracted with 2×100 mL of dichloromethane. The combined organic layerswere dried over sodium sulfate and concentrated under reduced pressure.The crude material was purified on silica chromatography (300 g Biotage™column) and eluted with 15-80% ethyl acetate in hexanes to yieldCompound A and Compound B both as white solids. LC-MS: 314.21 (M+1).

Step B: 1-(Cyclopropylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole

A solution of Compound A (60 mg, 0.19 mmol) in dichloromethane (1.0 mL)was treated with trifluoroacetic acid (1.0 mL) at room temperature.After 1.5 h, the reaction was concentrated and purified on silica gelcolumn using 5-10% methanol and 0.5-1% NH₄OH in dichloromethane to givethe title compound as an amber foam. ¹H NMR (500 MHz, CD₃OD): δ1.14-1.23 (m, 2H); 1.31-1.38 (m, 2H); 2.91-2.97 (m, 1H); 4.01-4.05 (m,2H); 4.20-4.24 (m, 2H); 7.60 (s, 1H). LC-MS: 214.13 (M+1).

2-(Cyclopropylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole

A solution of Compound B (205 mg, 0.65 mmol) in dichloromethane (4.0 mL)was treated with trifluoroacetic acid (4.0 mL) at room temperature.After 1.5 h, the reaction was concentrated and neutralized with 2Nammonium hydroxide in methanol to give the title compound as brownsyrup. ¹H NMR (500 MHz, CD₃OD): δ 1.17-1.23 (m, 2H); 1.31-1.38 (m, 2H);2.84-2.91 (m, 1H); 3.96-3.99 (m, 4H); 7.82 (s, 1H). LC-MS: 214.13 (M+1).

EXAMPLE 1

(2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amineStep A: tert-Butyl{(2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-yl}carbamate

A mixture of Intermediate 2 (26.3 g, 80 mmol) and2-(methylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole(Intermediate 5) (15.07 g, 80 mmol) in anhydrous methanol (1.5 L) wasstirred at room temperature for 2 h. To the resulting white suspensionwas added decaborane (2.95 g, 24.15 mmol) and the mixture was stirred atroom temperature overnight. Methanol was removed and the residue waspurified on two 65i Biotage™ columns eluting with 5-50% ethyl acetate indichloromethane to afford the title compound as a white solid. LC-MS:499.10 (M+1).

Step B:(2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine

Removal of the BOC group in the product from Step A (13.78 g, 27.67mmol) was accomplished with trifluoroacetic acid (100 ml) indichloromethane (200 mL) at room temperature. After stirring for 2 h,the reaction was concentrated and neutralized with 25% MeOH and 2.5%ammonium hydroxide in dichloromethane. Solvents were removed underreduced pressure and the resulting crude material was purified on a 65iBiotage™ column eluting with 1.25-5% MeOH and 0.125-0.5% ammoniumhydroxide in dichloromethane. The isolated material was further purifiedby recrystallization from 5:1 EtOAc/CH₂Cl₂ at 60° C. The crystallineproduct was washed with cold 2:1 EtOAc/hexanes to give the titlecompound as a light brown solid. ¹H NMR (500 MHz, CD₃OD): 1.71 (q, 1H,J=12 Hz), 2.56-2.61 (m, 1H), 3.11-3.18 (m, 1H), 3.36-3.40 (m, 1H), 3.48(t, 1H, J=12 Hz), 3.88-3.94 (m, 4H), 4.30-4.35 (m, 1H), 4.53 (d, 1H,J=12 Hz), 7.14-7.23 (m, 2H), 7.26-7.30 (m, 1H), 7.88 (s, 1H). LC-MS:399.04 (M+1).

EXAMPLE 2

(2R,3S,5R)-2-(2,4,5-Trifluorophenyl)-5-[2-methylsulfonyl-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amineStep A: tert-Butyl{(2R,3S,5R)-2-(2,4,5-Trifluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-e]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-yl}carbamate

A mixture of Intermediate 1 (516 mg, 1.5 mmol) and2-(methylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-e]pyrazole(Intermediate 5) (280 mg, 1.5 mmol) in anhydrous methanol (70 ml) wasstirred for 30 min before adding decaborane (54.8 mg, 0.45 mmol). Thereaction was stirred at room temperature for 18 h. The reaction wasconcentrated and purified on 40M Biotage™ silica column eluting with0-10% ethyl acetate in dichloromethane to wash out the minor isomer and1.25% methanol in dichloromethane to elute the title compound which wasobtained as a white solid. LC/MS: 517.05 (M+1).

Step B:(2R,3S,5R)-2-(2,4,5-Trifluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine

Intermediate obtained in Step A above (379 mg, 0.734 mmol) indichloromethane (20 mL) was treated with trifluoroacetic acid (10 mL) atroom temperature. After 2 h, the reaction was concentrated and the crudematerial was purified on a silica gel column (40S Biotage™) eluting within 0-2% methanol, containing 10% NH₄OH, in dichloromethane to give thetitle compound as a white solid. ¹H NMR (500 MHz, CD₃OD): δ 1.50 (q, 1H,J=12 Hz); 2.43-2.49 (m, 1H); 2.88 (td, 1H, J=12, 6 Hz); 3.11-3.18 (m,1H); 3.34 (s, 3H); 3.40 (t, 1H, J=12 Hz); 3.48-3.92 (m, 4H); 4.23-4.28(m, 2H); 7.14-7.20 (m, 1H); 7.36-7.42 (m, 1H); 7.86 (s, 1H). LC-MS:417.12 (M+1).

EXAMPLE 3

(2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[1-(cyclopentylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4M-yl]tetrahydro-2H-pyran-3-amineStep A: tert-Butyl{(2R,3S,5R)-2-(2,5-difluorophenyl)-5-[1-(cyclopentylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-yl}carbamate

A mixture of Intermediate 2 (50.1 mg, 0.15 mmol) and1-(cyclopentylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole(Intermediate 4) (35 mg, 0.15 mmol) in anhydrous methanol (1.0 mL) wasstirred for 30 min before adding decaborane (5.32 mg, 0.044 mmol). Afterstirring at room temperature for 18 h, the reaction mixture wasconcentrated and purified on preparative thin layer chromatographyplates eluting with 50% ethyl acetate in dichloromethane to yield thetitle compound as a colorless film. LC-MS: 553.46 (M+1).

Step B:(2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[1-(cyclopentylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine

A solution of the intermediate obtained in Step A above (49 mg, 0.089mmol) in dichloromethane (4 mL) was treated with trifluoroacetic acid (2mL) at room temperature. After 1.5 h, the reaction mixture wasconcentrated and purified by preparative thin layer chromatographyeluting with 5% methanol containing 10% NH₄OH in dichloromethane to givethe title compound.

¹H NMR (500 MHz, CD₃OD): δ 1.54 (q, 1H, J=12 Hz); 1.62-1.77 (m, 4H);1.92-2.08 (m, 4H); 2.42-2.49 (m, 1H); 2.98-3.06 (m, 1H); 3.07-3.14 (m,1H); 3.40 (t, 1H, J=12 Hz); 3.87-3.91 (m, 2H); 4.01-4.08 (m, 1H);4.09-4.17 (m, 2H); 4.20-4.27 (m, 1H); 4.34 (d, 1H, J=10 Hz); 7.08-7.18(m, 2H); 7.20-7.25 (m, 1H); 7.64 (s, 1H). LC-MS: 453.10 (M+1).

EXAMPLE 4

(2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(cyclopentylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-aminetrifluoroacetate salt Step A: tert-Butyl{(2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2-(cyclopentylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-yl}carbamate

A mixture of Intermediate 2 (92 mg, 0.28 mmol) and2-(cyclopentylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole(Intermediate 4) (68 mg, 0.28 mmol) in anhydrous methanol (2.0 mL) wasstirred for 30 min before adding decaborane (10.3 mg, 0.085 mmol). Afterstirring at room temperature for 18 h, the reaction mixture wasconcentrated and purified on preparative thin layer chromatographyplates eluting with 30% ethyl acetate in dichloromethane to yield thetitle compound as white solid. LC-MS: 553.37 (M+1).

Step B:(2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(cyclopentylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-aminetrifluoroacetate salt

A solution of the intermediate obtained in Step A above (90 mg, 0.16mmol) in dichloromethane (6 mL) was treated with trifluoroacetic acid (3mL) at room temperature. After 1.5 h, the reaction mixture wasconcentrated to give the title compound. ¹H NMR (500 MHz, CD₃OD): δ1.61-1.74 (m, 4H); 1.92-2.08 (m, 4H); 2.11 (q, 1H, J=12 Hz); 2.78-2.84(m, 1H); 3.68 (td, 1H, J=12, 4 Hz); 3.78 (t, 1H, J=12 Hz); 3.88-3.96 (m,1H); 4.02-4.10 (m, 1H); 4.49-4.67 (m, 5H); 4.71 (d, 1H, J=12 Hz);7.19-7.27 (m, 2H); 7.28-7.33 (m, 1H); 8.09 (s, 1H). LC-MS: 453.04 (M+1).

EXAMPLE 5

(2R,3S,5R)-2-(2,4,5-Trifluorophenyl)-5-[2-(cyclopentylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-aminetrifluoroacetate salt Step A: tert-Butyl{(2R,3S,5R)-2-(2,4,5-trifluorophenyl)-5-[2-(cyclopentylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-yl}carbamate

A mixture of Intermediate 1 (97 mg, 0.28 mmol) and2-(cyclopentylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole(Intermediate 4) (68 mg, 0.28 mmol) in anhydrous methanol (2.0 mL) wasstirred for 30 min before adding decaborane (10.3 mg, 0.085 mmol). Afterstirring at RT for 18 h, the reaction mixture was concentrated andpurified on preparative thin layer chromatography plates eluting with30% ethyl acetate in dichloromethane to yield the title compound as awhite solid. LC-MS: 571.34 (M+1).

Step B:(2R,3S,5R)-2-(2,4,5-Trifluorophenyl)-5-[2-(cyclopentylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-aminetrifluoroacetate salt

A solution of the intermediate obtained in Step A above (93 mg, 0.16mmol) in dichloromethane (6 mL) was treated with trifluoroacetic acid (3mL) at room temperature. After 1.5 h, the reaction was concentrated togive the title compound.

¹H NMR (500 MHz, CD₃OD): δ 1.71-1.76 (m, 4H); 1.92-2.08 (m, 4H); 2.12(q, 1H, J=12 Hz); 2.79-2.85 (m, 1H); 3.64 (td, 1H, J=10, 6 Hz); 3.79 (t,1H, J=12 Hz); 3.90-3.98 (m, 1H); 4.02-4.10 (m, 1H); 4.48-4.54 (m, 1H);4.57-4.72 (m, 5H); 7.24-7.33 (m, 1H); 7.46-7.54 (m, 1H); 8.10 (s, 1H).LC-MS: 471.04 (M+1).

EXAMPLE 6

(2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[1-(cyclopropylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-aminetrifluoroacetate salt Step A: tert-Butyl{(2R,3S,5R)-2-(2,5-difluorophenyl)-5-[1-(cyclopropylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-yl}carbamate

A mixture of Intermediate 2 (26 mg, 0.08 mmol) and1-(cyclopropylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole(Intermediate 6) (18 mg, 0.084 mmol) in anhydrous methanol (1.0 mL) wasstirred for 30 min before adding decaborane (2.9 mg, 0.024 mmol). Afterstirring at room temperature for 18 h, the reaction mixture wasconcentrated and purified on preparative thin layer chromatographyplates eluting with 50% ethyl acetate in dichloromethane to yield thetitle compound as a white solid. LC-MS: 525.2 (M+1).

Step B:(2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[1-(cyclopropylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-aminetrifluoroacetate salt

A solution of the intermediate obtained in Step A above (52 mg, 0.099mmol) in dichloromethane (2 mL) was treated with trifluoroacetic acid (1mL) at room temperature. After 1.5 h, the reaction mixture wasconcentrated and purified on reverse phase HPLC using H₂O/acetonitrilecontaining 0.05 TFAv/v, to give the title compound. ¹H NMR (500 MHz,CD₃OD): δ 1.21-1.27 (m, 2H); 1.38-1.43 (m, 2H); 2.06 (q, 1H, J=14 Hz);2.73-2.79 (m, 1H); 2.29-3.06 (m, 1H); 3.57-3.64 (m, 1H); 3.74 (t, 1H,J=12 Hz); 3.81-3.90 (m, 1H); 4.44-4.54 (m, 3H); 4.69 (d, 1H, J=12 Hz);4.71-4.81 (m, 2H); 7.18-7.26 (m, 2H); 7.27-7.32 (m, 1H); 7.74 (s, 1H).LC-MS: 425.21 (M+1).

EXAMPLE 7

(2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-cyclopropylsulfonyl-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-aminetrifluoroacetate salt Step A: tert-Butyl{(2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2-(cyclopropylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-yl}carbamate

A mixture of Intermediate 2 (1.10 g, 3.38 mmol) and2-(cyclopropylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole(Intermediate 6) (600 mg, 2.81 mmol) in anhydrous methanol (80 mL) wasstirred for 30 min before adding decaborane (206 mg, 1.7 mmol). Afterstirring at RT for 18 h, the reaction was concentrated and purified onpreparative thin layer chromatography plates eluting with 5% methanoland 1% NH₄OH in dichloromethane to yield the title compound as a whitesolid. LC-MS: 425.01 (M+1).

Step B:(2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(cyclopropylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-aminetrifluoroacetate salt

A solution of the intermediate from Step A above (93 mg, 0.16 mmol) indichloromethane (6 mL) was treated with trifluoroacetic acid (3 ml) atroom temperature. After 1.5 h, the reaction mixture was concentrated togive the title compound. ¹H NMR (500 MHz, CD₃OD): δ 1.17-1.23 (m, 2H);1.34-1.40 (m, 2H); 2.08 (q, 1H, J=12 Hz); 2.80 (d, 1H, J=12 Hz);2.91-2.97 (m, 1H); 3.58-3.66 (m, 1H); 3.76 (t, 1H, J=12 Hz), 3.82-3.90(m, 1H); 4.47-4.62 (m, 5H); 4.70 (d, 1H, J=10 Hz); 7.18-7.26 (m, 2H);7.28-7.32 (m, 1H); 8.05 (s, 1H). LC-MS: 425.01 (M+1).

EXAMPLE 8

(2R,3S,5R)-2-(2,4,5-Trifluorophenyl)-5-[2-(cyclopropylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-aminetrifluoroacetate salt Step A: tert-Butyl{(2R,5R)-2-(2,4,5-trifluorophenyl)-5-[(2-(cyclopropylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-yl}carbamate

A mixture of Intermediate 1 (94 mg, 0.27 mmol) and2-(cyclopropylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole(Intermediate 6) (58 mg, 0.27 mmol) in anhydrous methanol was stirredfor 30 min before adding decaborane (10 mg, 0.083 mmol). After stirringat room temperature for 18 h, the reaction mixture was concentrated andpurified on preparative thin layer chromatography plates eluting with50% ethyl acetate in dichloromethane to yield the title compound as awhite solid. LC-MS: 543.30 (M+1).

Step B:(2R,3S,5R)-2-(2,4,5-Trifluorophenyl)-5-[2-(cyclopropylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-aminetrifluoroacetate salt

A solution of the product obtained in Step A above (74 mg, 0.14 mmol) indichloromethane (6 mL) was treated with trifluoroacetic acid (3 mL) atroom temperature. After 1.5 h, the reaction mixture was concentrated togive the title compound. NMR (500 MHz, CD₃OD): δ □1.18-1.24 (m, 2H);1.35-1.40 (m, 2H); 2.12 (q, 1H, J=12 Hz); 2.79-2.86 (m, 1H); 2.92-2.98(m, 1H); 3.64 (td, 1H, J=12, 6 Hz); 3.79 (t, 1H, J=12 Hz); 3.90-3.98 (m,1H); 4.48-4.54 (m, 1H); 4.57-4.72 (m, 5H); 7.25-7.32 (m, 1H); 7.46-7.53(m, 1H); 8.08 (s, 1H). LC-MS: 443.04 (M+1).

The following additional Examples were made by essentially following themethods described for Examples 1 through 8.

Example R^(a) R^(b) LC-MS 9 —CH₂CH₃ H 413.01 10 —CH₂CH₃ F 431.15 11—CH(CH₃)₂ H 427.30 12 —CH(CH₃)₂ F 445.04 13 —CH₂CH₂CH₃ H 427.11 14—CH₂CH₂CH₃ F 445.13 15

H 465.23 16

H 462.05 17

H 529.2Example of a Pharmaceutical Formulation

As a specific embodiment of an oral pharmaceutical composition, a 100 mgpotency tablet is composed of 100 mg of any one of the Examples, 268 mgmicrocrystalline cellulose, 20 mg of croscarmellose sodium, and 4 mg ofmagnesium stearate. The active, microcrystalline cellulose, andcroscarmellose are blended first. The mixture is then lubricated bymagnesium stearate and pressed into tablets.

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.For example, effective dosages other than the particular dosages as setforth herein above may be applicable as a consequence of variations inresponsiveness of the mammal being treated for any of the indicationswith the compounds of the invention indicated above. The specificpharmacological responses observed may vary according to and dependingupon the particular active compounds selected or whether there arepresent pharmaceutical carriers, as well as the type of formulation andmode of administration employed, and such expected variations ordifferences in the results are contemplated in accordance with theobjects and practices of the present invention. It is intended,therefore, that the invention be defined by the scope of the claimswhich follow and that such claims be interpreted as broadly as isreasonable.

What is claimed is:
 1. A method of treating diabetes in a patientcomprising administering to a patient in need thereof a therapeuticallyeffective amount of a compound which is:

or a pharmaceutically acceptable salt in combination with insulin.